1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives

ABSTRACT

The invention relates to 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative having the general Formula I 
                         
wherein R 1  is H, (C 1-6 )alkyl (optionally substituted with oxo, (C 1-3 )alkyloxy, (C 1-3 )alkyloxycarbonyl, halogen or CN), (C 3-6 )cycloalkyl or (C 3-6 )cycloalkyl(C 1-3 )alkyl, each cycloalkyl ring optionally comprising a heteroatom selected from O and S; R 2  and R 3  are independently H or (C 1-3 )alkyl; or R 2  and R 3  form together with the carbon atom to which they are bound a (C 3-5 )cycloalkyl group; R 4  is H or 1 to 3 F substituents; R 5  is H or 1 to 4 F substituents; R 6  and R 7  are independently H or F; X represents R 8 , OR 8 , NR 8 R 9 ,
 
                         
R 8  is (C 5-7 )cycloalkyl optionally comprising a heteroatom selected from O, S, SO and SO 2 ; R 9  is H or (C 1-4 )alkyl; R 10  represents 1-3 substituents independently selected from H, (C 1-3 )alkyl, halogen, oxo, CN and CF 3 ; Y is CF 2 , O, S, SO or SO 2 ; or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions comprising the same, as well as to the use of said 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.

This application is a non-provisional application that claims priorityunder 35 U.S.C. §119(e) of provisional application U.S. Ser. No.61/119,211 filed Dec. 2, 2008, the contents of which are herebyincorporated by reference in its entirety.

BACKGROUND

The present invention relates to1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives, topharmaceutical compositions comprising the same and to the use of these1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives intherapy, especially in the treatment of pain.

Pain is an unpleasant sensory and emotional experience associated withactual or potential tissue damage. Pain can be nociceptive orneuropathic in origin. Pain experienced as a consequence of arthritis isgenerally nociceptive in nature, caused by inflammation of tissue andstimulation of nociceptors. Major indications driving prevalence ofnociceptive pains are low back pain, osteoarthritis, post-operativepain, and cancer-related pain. Major unmet needs for nociceptive painare for improved efficacy and fewer side effects. The chronic painmarket is currently dominated by non-steroidal anti-inflammatory drugs(NSAIDs) and cyclo-oxygenase COX-2 inhibitors. NSAIDs provide adequateanalgesia to relieve mild to moderate pain and usually have greatereffectiveness in inflammatory pain. Individual NSAIDs vary in theirefficacy, and these variations are partly determined by differingCOX-1/COX-2 selectivities. Consequently, patients may require to betreated with several different drugs before their pain is adequatelytreated. Side effects associated with drug therapy are an importantfactor in treatment choice, especially as many pain syndromes arelong-term chronic conditions.

The most common side effects of NSAIDs are constipation and indigestion;most anti-inflammatory drugs are acidic in nature and promote acidproduction in the stomach. Other, serious side effects aregastrointestinal complications such as gastric ulcers, mucosal damageand peptic erosion. NSAIDs are thought to account for as many as 107,000hospitalizations and 16,500 deaths due to ulcer complications in the USeach year (Singh, Recent considerations in nonsteroidalanti-inflammatory drug gastropathy. Am. J. Med., 1998, 105: 31S-38S).Whilst COX-2 inhibitors have an improved gastrointestinal side effectprofile, their use has been associated with increased risk of myocardialinfarction and stroke and increased risk of hypertension.

Neuropathic pain, defined as chronic pain caused by injury, disease ordysfunction of the nervous system, is present in ˜1% of the population;the largest patient populations include those with painful diabeticperipheral neuropathy, and those with neuralgia that persists after anattack of herpes zoster (post-herpetic neuralgia). It is characterizedby a complex combination of symptoms, including spontaneous pain thatcan occur in the absence of tissue damage. Patients suffering fromneuropathic pain also have increased sensitivity both to stimulinormally perceived as painful (hyperalgesia), as well as to stimuli thatdo not normally provoke pain (allodynia). These symptoms are oftenrefractory to conventional analgesic therapies, with most patientsachieving incomplete relief of their symptoms. Currently,antidepressants, anticonvulsants and opioids remain first-linetreatment, with gabapentin as the gold standard. All of these drugs havesignificant side-effects that are dose limiting. In addition, efficacyis a considerable problem in the neuropathic pain market with currenttreatments showing a maximum of 50% reduction in overall pain scoresfrom baseline. Consequently, there remains an unmet medical need foragents that have higher efficacy/responder rate, and with reducedside-effects compared with currently used drugs.

Emerging clinical evidence, as well as anecdotal reports from patientsself-medicating with cannabis, suggest that cannabinoid receptoragonists may have a role in treating pain (Fox A, Bevan S., Therapeuticpotential of cannabinoid receptor agonists as analgesic agents. ExpertOpin Investig Drugs, 2005, 14, 695-703). GW Sativex, a 1:1 ratio ofΔ⁹-THC and cannabidiol in an oromucosal spray formulation that allowsindividualised dosing for the treatment of neuropathic pain has beenlaunched by GW Pharmaceuticals. Clinical studies with Sativex havedemonstrated efficacy in patients with intractable pain (chronicneuropathic pain, pain due to brachial plexus nerve injury, allodynicperipheral neuropathic pain and advanced cancer pain), rheumatoidarthritis and symptoms associated with multiple sclerosis (pain,spasticity, poor bladder control and disrupted sleep; (Barnes M P. 2006.Sativex: clinical efficacy and tolerability in the treatment of symptomsof multiple sclerosis and neuropathic pain. Expert Opin. Pharmacother.7(5): 607-615).

Two types of cannabinoid receptors have been identified. The cannabinoidCB1 receptor is located primarily in the central nervous system (CNS;brain and spinal cord), but is also expressed by peripheral neurones andto a lower extent in other peripheral tissues. The cannabinoid CB2receptor is mainly confined to the periphery, mostly in immune cells(Howlett, A. C. et al, International Union of Pharmacology. XXVII.Classification of Cannabinoid Receptors. Pharmacol. Rev. 54, 161-202,2002). While the conventional CB1 receptor agonists and CB1/CB2 receptoragonists, such as tetrahydrocannabinol (THC) are highly effective inmodels of pain in animals, their therapeutic utility in man is limitedby undesired CNS side-effects, such as psychoactive effects, and byabuse potential (Chapman, V. and Finn, D. P. “Analgesic effects ofcannabinoids: sites and mechanism of action.” Rev. Analg. 7, 25-39,2003).

Recent literature evidence suggests that selective activation of the CB2receptor may constitute a novel strategy for treating pain andinflammation without undesirable CNS side effects. (Guindon, J. andHohmann, A., “Cannabinoid CB2 receptors: a therapeutic target for thetreatment of inflammatory and neuropathic pain”, Br. J. Pharmacol.,2008, 153, 319-334). Activation of the CB2 receptor was found to inhibitacute, inflammatory and neuropathic pain responses in animal models(Whiteside G. T., Lee G. P., Valenzano K. J. “The role of thecannabinoid CB2 receptor in pain transmission and therapeutic potentialof small molecule CB2 receptor agonists, Current Med. Chem., 2007, 14,917-936). CB2 knock-out mice studies also support a role for CB2receptors in pain (Malan T P, Jr, Ibrahim M M, Lai J, Vanderah T W,Makriyannis A and Porreca F. CB2 cannabinoid receptor agonists: painrelief without psychoactive effects? Curr. Opin. Pharmacol. 2003; 3:62-67).

The cellular mechanisms contributing to CB2-mediated antinociception arenot yet clear, but it has been proposed that activation of CB2 receptorsaffects inflammatory pain indirectly via modulation of immune cellactivity, resulting in decreased release of mediators at the local siteof inflammation. In addition to a peripheral effect, recent publicationssuggest that CB2 receptor agonists can also interact with CB2 receptorsexpressed on peripheral neurons and activated microglia to modulate paintransmission. (Beltramo et al., 2006. CB2 receptor-mediatedantihyperalgesia: possible direct involvement of neural mechanisms. EurJ Neurosci. 23(6):1530-80; Romero-Sandoval & Eisenach, 2007. Spinalcannabinoid receptor type 2 activation reduces hypersensitivity andspinal cord glial activation after paw incision. Anesthesiology106(4):787-94).

In summary, CB2 receptor agonists may be suitable for the treatment ofacute and chronic pain conditions, such as osteoarthritis, rheumatoidarthritis and acute post-operative pain and neuropathic pain. Theabsence of catalepsy with CB2 agonists in preclinical models showspromise for the treatment of acute and chronic pain without undesiredCNS side effects

Thus, there is a need for selective CB2 cannabinoid receptor agonists astherapeutic agents in the treatment of pain.

SUMMARY OF THE INVENTION

To this end the present invention provides a novel structural class of1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative having thegeneral Formula I

whereinR₁ is H, (C₁₋₆)alkyl (optionally substituted with oxo, (C₁₋₃)alkyloxy,(C₁₋₃)alkyloxycarbonyl, halogen or CN), (C₃₋₆)cycloalkyl or(C₃₋₆)cycloalkyl(C₁₋₃)alkyl, each cycloalkyl ring optionally comprisinga heteroatom selected from O and S;R₂ and R₃ are independently H or (C₁₋₃)alkyl; orR₂ and R₃ form together with the carbon atom to which they are bound a(C₃₋₅)cycloalkyl group;R₄ is H or 1 to 3 F substituents;R₅ is H or 1 to 4 F substituents;R₆ and R₇ are independently H or F;X represents R₈, OR₈, NR₈R₉,

R₈ is (C₅₋₇)cycloalkyl optionally comprising a heteroatom selected fromO, S, SO and SO₂;R₉ is H or (C₁₋₄)alkyl;R₁₀ represents 1-3 substituents independently selected from H,(C₁₋₃)alkyl, halogen, oxo, CN and CF₃;Y is CF₂, O, S, SO or SO₂;or a pharmaceutically acceptable salt thereof, as agonists of thecannabinoid CB2 receptor, which can be used in the treatment of painsuch as for example peri-operative pain, chronic pain, neuropathic pain,cancer pain and pain and spasticity associated with multiple sclerosis.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1. The effect of acute oral administration of compound 12 onneuropathy-induced mechanical allodynia in rats.

The reading at 0 min denotes the post-surgery withdrawal threshold (thedifference between the pre-surgery and 0 min reading denotes thedevelopment of mechanical allodynia), this reading was followed byadministration of test compound. Data are expressed as mean±s.e.m.

DESCRIPTION OF THE INVENTION

The term (C₁₋₆)alkyl as used in the definition of Formula I means abranched or unbranched alkyl group having 1-6 carbon atoms, like hexyl,pentyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl andmethyl.

The term (C₁₋₄)alkyl likewise means a branched or unbranched alkyl grouphaving 1-4 carbon atoms, like n-butyl, tert-butyl, propyl, isopropyl,ethyl and methyl.

The term (C₁₋₃)alkyl likewise means a branched or unbranched alkyl grouphaving 1-3 carbon atoms, like propyl, isopropyl, ethyl and methyl.

The meaning of the (C₁₋₃)alkyl in the terms (C₁₋₃)alkyloxy and(C₁₋₃)alkyloxycarbonyl is as defined above.

The term (C₃₋₆)cycloalkyl means a cycloalkyl group having 3-6 carbonatoms, like cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.

The term (C₃₋₅)cycloalkyl means a cycloalkyl group having 3-5 carbonatoms, like cyclopentyl, cyclobutyl and cyclopropyl.

The term (C₅₋₇)cycloalkyl likewise means a cycloalkyl group having 5-7carbon atoms. The preferred (C₅₋₇)cycloalkyl is cyclohexyl.

The term halogen means F, Cl, Br or I.

There is a preference for1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives accordingto Formula I, wherein R₂, R₃ and R₅ are H. Also preferred are thecompounds according to Formula I wherein R₁ is (C₁₋₄)alkyl. Furtherpreferred are the compounds according to Formula I wherein X representsNR₈R₉,

More preferred are the compounds of formula I wherein X is NR₈R₉ and R₈is cyclohexyl optionally comprising a heteroatom selected from O and S.

Further preferred are compounds wherein R₄ is a F substituent at theposition ortho to the CR₆R₇X group.

Specifically preferred 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dionederivatives of the invention are:

-   3-Isobutyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-isobutyl-1-(4-(6-(morpholinomethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   1-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione;-   1-(4-(6-((1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)methyl)pyridin-2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione;-   1-(4-(6-((1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)methyl)-5-fluoropyridin-2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione;-   3-Isobutyl-1-(4-(6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-Ethyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-Ethyl-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-ethylimidazolidine-2,4-dione;-   1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)pyridin-2-yl)benzyl)-3-ethylimidazolidine-2,4-dione;-   1-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-propylimidazolidine-2,4-dione;-   1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-propylimidazolidine-2,4-dione;-   3-(2,2-Difluoroethyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-(2,2-Difluoroethyl)-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-(Cyclopropylmethyl)-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-(Cyclopropylmethyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-(2-Oxopropyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   1-(4-(5-Fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(2-oxopropyl)imidazolidine-2,4-dione;-   1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-(2-oxopropyl)imidazolidine-2,4-dione;-   3-Isopropyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-isopropylimidazolidine-2,4-dione;-   1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)pyridin-2-yl)benzyl)-3-isopropylimidazolidine-2,4-dione;-   3-Cyclopropyl-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-Cyclopropyl-1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-Cyclobutyl-1-(4-(5-fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-Cyclobutyl-1-(4-(6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-Cyclobutyl-1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   3-Cyclobutyl-1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;-   1-(4-(6-(Piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;-   1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;-   1-(4-(6-((Tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-(2,2,2-trifluoro-ethyl)imidazolidine-2,4-dione;-   1-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;    or a pharmaceutically acceptable salt thereof.

The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives of theinvention having Formula I can be prepared by methods known in the artof organic chemistry.

Compounds of the invention can for example be obtained from a Suzukicoupling reaction using potassium carbonate and a palladium (0) complexsuch as Pd(Ph₃P)₄ between a 2-bromopyridine derivative of Formula II,wherein R₄, R₆, R₇ and X have the meaning as previously defined, with aboronic acid derivative of Formula IV which is prepared from abenzylated imidazolidine of Formula III, wherein R₁, R₂, R₃ and R₅ havethe meaning as previously defined (see Scheme I). Compounds of FormulaII, wherein X represents R₈ and R₈ is (C₅₋₇)cycloalkyl comprising aheteroatom selected from S and O, can be prepared (see Scheme II) fromthe condensation of a pyridine dibromide derivative of formula 1,wherein R₄ has the meaning as previously defined, with a nitrilederivative of formula 2, wherein Z is

CH₂, O or S, to give the intermediate keto-derivative of formula 3,which can either be reduced via the hydrazide derivative of formula 4 toproduce the compound of formula IIb, corresponding to a compound offormula II wherein R₆ and R₇ are H, or which can be reduced with the aidof diethylaminosulfur trifluoride to give a compound of formula IIa,corresponding to a compound of formula II wherein R₆ and R₇ are F.

Conditions:

A: butyllithium/H₂SO₄ B: 4-methylbenzenesulfonyl hydrazide C:diisobutylaluminum hydride D: diethylaminosulfur trifluoride

Compounds of Formula II, wherein X represents OR₈ can be prepared asdepicted in Scheme III starting with bromination of a2-bromo-6-methylpyridine derivative of formula 5 with the aid ofN-bromosuccinimide/azo-di-isobutyronitrile to give the corresponding6-bromomethyl derivative of formula 6 which is reacted with an alcoholderivative of formula 7, wherein Z is CH₂, O or S, to give a compound offormula IIc.

Compounds of Formula II, wherein X represents NHR₈,

can be prepared using a reductive amination reaction, for instance withthe use of acetic acid/sodium triacetoxyborohydride, of a carbaldehydederivative of formula 8 with an appropriate amine derivative of formulaX-H.

Compounds of formula III can be prepared by coupling of the amino acidH₂N—C(R₂,R₃)—COOH with a 4-bromobenzaldehyde derivative of formula 9under reductive amination conditions to obtain the N-benzyl derivativeof formula 12, which is subsequently coupled with the amine H₂N—R₁,wherein R₁ has the previously defined meaning, with the aid of an amidebond forming reagent, such as dicyclohexylcarbodiimide (DCCI), TBTU orPyBOP or the like, to the amide derivative 13 from which theimidazolidine-2,4-dione derivative of formula III can be prepared by aring closure reaction using carbonyldiimidazole.

In an alternative route which is denoted in Scheme IV the4-bromobenzaldehyde derivative of formula 9 is coupled to the amino acidamide of formula H₂N—C(R₂,R₃)—CONH₂ under reductive amination conditionsto obtain the N-benzyl derivative of formula 10, which can be convertedto a compound of formula III by cyclisation using carbonyldiimidazoleand subsequent alkylation with a halogenide of formula Hal-R₁.

Conditions:

A: glycinamide hydrochloride/NaOH/NaBH₄. B: CDI/DMAP. C:R₁-halide/potassium carbonate D: glycine hydrochloride/NaOH/NaBH₄E:R₁-amine/o-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate. F: CDI/DMAP. G: bis(pinacolato)diboron/potassiumacetate/1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II)

The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives ofFormula I and their salts may contain at least one centre of chirality,and exist therefore as stereoisomers, including enantiomers anddiastereomers. The present invention includes the aforementionedstereoisomers within its scope and each of the individual R and Senantiomers of the compounds of Formula I and their salts, substantiallyfree base, i.e. associated with less than 5%, preferably less than 2%,in particular less than 1% of the other enantiomer, and mixtures of suchenantiomers in any proportions including the racemic mixtures containingsubstantially equal amounts of the two enantiomers.

Methods for asymmetric synthesis or chiral separation whereby the purestereo-isomers are obtained are well known in the art, e.g. synthesiswith chiral induction or starting from commercially available chiralsubstrates, or separation of stereo-isomers, for example usingchromatography on chiral media or by crystallisation with a chiralcounter-ion.

Pharmaceutically acceptable salts may be obtained by treating a freebase of a 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivativeof Formula I with a mineral acid such as hydrochloric acid, hydrobromicacid, phosphoric acid and sulfuric acid, or an organic acid such as forexample ascorbic acid, citric acid, tartaric acid, lactic acid, maleicacid, malonic acid, fumaric acid, glycolic acid, succinic acid,propionic acid, acetic acid and methane sulfonic acid.

The compounds of the invention may exist in unsolvated as well as insolvated forms with pharmaceutically acceptable solvents such as water,ethanol and the like. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purpose of the invention.

The present invention further provides pharmaceutical compositionscomprising a 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dionederivative according to general Formula I, or a pharmaceuticallyacceptable salt thereof, in admixture with one or more pharmaceuticallyacceptable auxiliaries, and optionally other therapeutic agents. Theterm “acceptable” means being compatible with the other ingredients ofthe composition and not deleterious to the recipients thereof.Compositions include e.g. those suitable for oral, sublingual,subcutaneous, intravenous, epidural, intrathecal, intramuscular,transdermal, pulmonary, local, ocular or rectal administration, and thelike, all in unit dosage forms for administration. A preferred route ofadministration is the oral route.

For oral administration, the active ingredient may be presented asdiscrete units, such as tablets, capsules, powders, granulates,solutions, suspensions, and the like.

For parenteral administration, the pharmaceutical composition of theinvention may be presented in unit-dose or multi-dose containers, e.g.injection liquids in predetermined amounts, for example in sealed vialsand ampoules, and may also be stored in a freeze dried (lyophilized)condition requiring only the addition of sterile liquid carrier, e.g.water, prior to use.

Mixed with such pharmaceutically acceptable auxiliaries, e.g. asdescribed in the standard reference, Gennaro, A. R. et al, Remington:The Science and Practice of Pharmacy (20th Edition, Lippincott Williams& Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing),the active agent may be compressed into solid dosage units, such aspills, tablets, or be processed into capsules, suppositories or patches.By means of pharmaceutically acceptable liquids the active agent can beapplied as a fluid composition, e.g. as an injection preparation, in theform of a solution, suspension, emulsion, or as a spray, e.g. a nasalspray.

For making solid dosage units, the use of conventional additives such asfillers, colorants, polymeric binders and the like is contemplated. Ingeneral any pharmaceutically acceptable additive which does notinterfere with the function of the active compounds can be used.Suitable carriers with which the active agent of the invention can beadministered as solid compositions include lactose, starch, cellulosederivatives and the like, or mixtures thereof, used in suitable amounts.For parenteral administration, aqueous suspensions, isotonic salinesolutions and sterile injectable solutions may be used, containingpharmaceutically acceptable dispersing agents and/or wetting agents,such as propylene glycol or butylene glycol. The invention furtherincludes a pharmaceutical composition, as described before, incombination with packaging material suitable for said composition, saidpackaging material including instructions for the use of the compositionfor the use as described before.

The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives of theinvention were found to be selective agonists of the CB2 receptor ascompared to the CB1 receptor, as determined in a human CB2 and CB1reporter assays using CHO cells. Methods to determine receptor bindingas well as in vitro biological activity of cannabinoid receptormodulators are well known in the art. In general, expressed receptor isincubated with the compound to be tested and binding or stimulation orinhibition of a functional response is measured.

To measure a functional response isolated DNA encoding the CB2 or CB1receptor gene, preferably the human receptor, is expressed in suitablehost cells. Such a cell might be the Chinese Hamster Ovary cell, butother cells are also suitable. Preferably the cells are of mammalianorigin.

Methods to construct recombinant CB2 or CB1 expressing cell lines arewell known in the art (Sambrook et al, Molecular Cloning: a LaboratoryManual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latestedition). Expression of the receptor is attained by expression of theDNA encoding the desired protein. Techniques for ligation of additionalsequences and construction of suitable expression systems are all, bynow, well known in the art. Portions or all of the DNA encoding thedesired protein can be constructed synthetically using standard solidphase techniques, preferably to include restriction sites for ease ofligation. Suitable control elements for transcription and translation ofthe included coding sequence can be provided to the DNA codingsequences. As is well known, expression systems are now available whichare compatible with a wide variety of hosts, including prokaryotic hostssuch as bacteria and eukaryotic hosts such as yeast, plant cells, insectcells, mammalian cells, avian cells and the like.

Cells expressing the receptor are then incubated with the test compoundto observe binding, or stimulation or inhibition of a functionalresponse.

Alternatively isolated cell membranes containing the expressed CB2 orthe CB1 receptor may be used to measure binding of compound.

For measurement of binding radioactively or fluorescently labelledcompounds may be used. The most widely used radiolabelled cannabinoidprobe is (³H)CP55940, which has approximately equal affinity for CB1 andCB2 binding sites.

Functional CB2 or CB1 agonist activity may be measured by determiningthe second messenger response, such as for example measurement ofreceptor mediated changes in cAMP or MAP kinase pathways. Thus, such amethod involves expression of the CB2 or CB1 receptor on the cellsurface of a host cell and exposing the cell to the test compound. Thesecond messenger response is then measured. The level of secondmessenger will be reduced or increased, depending on the effect of thetest compound upon binding to the receptor.

In addition to direct measurement of e.g. cAMP levels in the exposedcell, cells can be used which in addition to transfection with receptorencoding DNA are also transfected with a second DNA encoding a reportergene, the expression of which correlates with receptor activation. Ingeneral, reporter gene expression might be controlled by any responseelement reacting to changing levels of second messenger. Suitablereporter genes are e.g. LacZ, alkaline phosphatase, firefly luciferaseand green fluorescence protein. The principles of such transactivationassays are well known in the art and are described e.g. in Stratowa, C.,Himmler, A. and Czernilofsky, A. P., Curr. Opin. Biotechnol. 6, 574(1995). For selecting selective, active agonist compounds on the CB2receptor the EC₅₀ value for a compound is <10⁻⁵ M, preferably <10⁻⁷ Mand the selectivity over CB1 receptor agonist as defined as EC50(CB1)/EC50 (CB2) is >10, preferably >50.

The compounds may be used as analgesic agents in the treatment of painsuch as for example acute pain such as peri-operative pain, chronicpain, neuropathic pain, cancer pain, visceral pain, headache andspasticity associated with multiple sclerosis.

Cannabinoid agonists of the invention would also potentially be usefulin the treatment of other disorders including, (intestinal)inflammation, atopic dermatitis, liver diseases, respiratory disorders,allergies, oncology, epilepsy, migraine, osteoporosis, cardiovasculardisorders, acute neurodegenerative disorders, such as traumatic braininjury and stroke and slowly neurodegenerative disorders, such asAlzheimer's disease, multiple sclerosis and ALS (Parcher P, Batkai S,Kunos, G, The endocannabinoid system as an emerging target ofpharmacotherapy, Pharmacol Rev. 2006, 58(3):389-462).

The compounds could also be used in conjunction with other drugs, forexample analgesic drugs such as opioids and non-steroidalanti-inflammatory drugs (NSAIDs), including COX-2 selective inhibitors.

The compounds of the invention may be administered to humans in asufficient amount and for a sufficient amount of time to alleviate thesymptoms. Illustratively, dosage levels for humans can be in the rangeof 0.001-50 mg per kg body weight, preferably in a dosage of 0.01-20 mgper kg body weight.

The invention is illustrated by the following Examples.

Abbreviations: Boc: tert-butoxycarbonyl; CDCl₃: chloroform-d; DBU:1,8-diazabicyclo(5.4.0)undec-7-ene; CDI: N,N′-carbonyldiimidazole; DCCI:1,3-dicyclohexylcarbodiimide; DCM: dichloromethane; DIPEA:N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF:N,N-dimethylformamide; Et₃N or TEA: triethyl amine; Gly: glycinyl; HPLC:high performance liquid chromatography; HOAc: acetic acid; HOBt:1-hydroxybenzo-triazole; MeOH: methanol; Me₃SiCl or TMSCI:chlorotrimethylsilane; MS: mass spectrum; (PPh₃)₄Pd:tetrakis(triphenylphosphine)palladium(0); PyBOP:(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate;PyBrOP: bromo(tris pyrrolidino)phosphonium tetrafluorohosphate; TBTU:((benzotriazol-1-yloxy)-dimethylamino-methylene)-dimethyl-ammoniumtetrafluoro borate; TFA: trifluoroacetic acid; THF: tetrahydrofuran;TLC: thin layer chromatography.

Compound names were generated with Cambridgesoft's Chemdraw Ultra,version 9.0.7.

EXAMPLE 1 1-(4-bromobenzyl)-3-isobutylimidazolidine-2,4-dione

i) To a solution of 4-bromobenzaldehyde (100 g, 0.54 mol) andglycinamide hydrochloride (54 g, 0.48 mol) methanol/water (1500 ml,5.5/1) was added sodium hydroxide (21.6 g, 0.54 mol). After stirring for17 h at room temperature the reaction mixture was cooled to 0° C. Sodiumborohydride (38 g, 1.0 mol) was added and the mixture was stirred untila clear solution was obtained. The reaction was quenched by addition ofconcentrated hydrochloric acid until pH=3. After stirring for 17 h themixture was neutralized with a saturated aqueous solution of sodiumhydrogen carbonate and the product was extracted into dichloromethane.The combined organic phases were washed with water, brine, dried oversodium sulfate and concentrated under reduced pressure to afford2-(4-bromobenzylamino)acetamide (92 g).

ii) To a solution of the product obtained in the previous step (60.6 g,0.25 mol) in acetonitrile (1500 ml) were added CDI (81 g, 0.5 mol) DMAP(61 g, 0.5 mol). After stirring for 16 h at 60° C. the solution wascooled to room temperature and poured into an aqueous solution of 2Mhydrochloric acid. The product was extracted into ethyl acetate and thecombined organic phases were washed with water, brine, dried over sodiumsulfate and concentrated under reduced pressure. The remaining solid wasstirred with acetone. Filtration afforded1-(4-bromobenzyl)imidazolidine-2,4-dione (45 g) as a white solid. Theproduct was used in the following step without further purification.

iii) To a solution of the product obtained in the previous step (10 g,37.2 mmol) in DMF (90 ml) were added at room temperature, potassiumcarbonate (15.4 g, 111 mmol) and 1-bromo-2-methylpropane (8.08 ml, 74.3mmol). After 17 h stirring at 50° C. under a nitrogen atmosphere thereaction mixture was cooled to room temperature and filtered. The clearsolution was concentrated under reduced pressure. Column chromatographyafforded 1-(4-bromobenzyl)-3-isobutylimidazolidine-2,4-dione (10.9 g) asa white solid.

EXAMPLE 2

Following a procedure analogous to that described in Example 1, thefollowing compounds were prepared.

2A: 1-(4-Bromobenzyl)-3-methylimidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.50 (d, J=8.61 Hz, 2H), 7.14 (d, J=8.61 Hz,2H), 4.52 (s, 2H), 3.73 (s, 2H), 3.06 (s, 3H).

2B: 1-(4-Bromobenzyl)-3-ethylimidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.50 (d, J=8.22 Hz, 2H), 7.13 (d, J=8.22 Hz,2H), 4.52 (s, 2H), 3.71 (s, 2H), 3.59 (q, J=7.43 Hz, 2H), 1.24 (t,J=7.43 Hz, 3H).

2C: 1-(4-Bromobenzyl)-3-propylimidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.49 (d, J=8.22 Hz, 2H), 7.13 (d, J=8.22 Hz,2H), 4.51 (s, 2H), 3.72 (s, 2H), 3.50 (dd J=7.43 and 6.26 Hz, 2H),1.72-1.60 (m, 2H), 0.93 (t, J=7.43 Hz, 3H).

2D: 1-(4-Bromobenzyl)-3-(2,2-difluoroethyl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.51 (d, J=8.22 Hz, 2H), 7.14 (d, J=8.22 Hz,2H), 6.21-5.87 (tt, J=55.95, 4.70 and 4.30 Hz, 1H), 4.53 (s, 2H), 3.90(td, J=13.70 and 4.30 Hz, 2H), 3.80 (s, 2H).

2E: 1-(4-Bromobenzyl)-3-(cyclopropylmethyl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.50 (d, J=8.22 Hz, 2H), 7.15 (d, J=8.22 Hz,2H), 4.53 (s, 2H), 3.74 (s, 2H), 3.56 (d, J=7.44 Hz, 2H), 1.23-1.12 (m,1H), 0.54-0.45 (m, 2H), 0.38-0.32 (m, 2H).

2F: 1-(4-Bromobenzyl)-3-(cyclobutylmethyl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.49 (d, J=8.22 Hz, 2H), 7.13 (d, J=8.22 Hz,2H), 4.50 (s, 2H), 3.71 (s, 2H), 3.57 (d, J=7.43 Hz, 2H), 2.75-2.62 (m,1H), 2.08-1.97 (m, 2H), 1.92-1.70 (m, 4H).

2G: 1-(4-Bromo-benzyl)-3-(2-methoxyethyl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.49 (d, J=8.22 Hz, 2H), 7.14 (d, J=8.22 Hz,2H), 4.52 (s, 2H), 3.77-3.72 (m, 4H), 3.60 (t, J=5.87 Hz, 2H), 3.36 (s,3H).

2H: methyl 2-(3-(4-bromobenzyl)-2,5-dioxoimidazolidin-1-yl)acetate

1H NMR (400 MHz, CDCl3): δ 7.50 (d, J=8.22 Hz, 2H), 7.15 (d, J=8.22 Hz,2H), 4.55 (s, 2H), 4.30 (s, 2H), 3.83 (s, 2H), 3.78 (s, 3H).

2L: 1-(4-Bromo-benzyl)-3-(2-oxopropyl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.51 (d, J=8.61 Hz, 2H), 7.15 (d, J=8.61 Hz,2H), 4.54 (s, 2H), 4.35 (s, 2H), 3.83 (s, 2H), 2.25 (s, 3H).

EXAMPLE 3 1-(4-Bromobenzyl)-3-isopropylimidazolidine-2,4-dione

i) To a solution of glycine (8.11 g, 108 mmol) in water (40 ml) wereadded an aqueous solution of sodium hydroxide (108 mmol, 15 ml) and asolution of 4-bromobenzaldehyde (20 g, 108 mmol) in methanol (240 ml).After 30 minutes stirring at room temperature sodium borohydride (4.09g, 108 mmol) was added portionwise to this suspension. After 18 hstirring at room temperature the reaction mixture was concentrated underreduced pressure and the resulting aqueous phase was washed with diethylether. The aqueous phase was neutralized by the addition of an aqueoussolution of 2M hydrochloric acid. The resulting precipitate wascollected by filtration, washed with water and diethyl ether. Drying thewhite solid afforded 2-(4-bromobenzylamino)acetic acid (14.2 g). Theproduct was used in the following step without further purification.

ii) To a suspension of the product obtained in the previous step (1.7 g,6.96 mmol) in dichloromethane (20 ml) were added triethylamine (1.94 ml,13.9 mmol), isopropylamine (0.65 ml, 7.66 mmol) ando-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (3.18 g, 8.36 mmol). After 17 h stirring at roomtemperature the reaction mixture was concentrated under reducedpressure. Column chromatography afforded2-(4-bromobenzylamino)-N-isopropylacetamide (1.95 g).

iii) To a solution of the product obtained in the previous step (1.95 g,6.96 mmol) in acetonitrile were added (diimidazol-1-yl)ketone (2.26 g,13.9 mmol) and 4-dimethylaminopyridine (1.70 g, 13.9 mmol). After 17 hstirring at 60° C., the reaction mixture was cooled to room temperatureand quenched by addition of a saturated aqueous solution of sodiumhydrogen carbonate. The product was extracted into ethylacetate and thecombined organic phases were washed with water, brine and dried oversodium sulfate. Column chromatography afforded the title compound1-(4-bromobenzyl)-3-isopropylimidazolidine-2,4-dione (1.8 g) as a lightyellow oil.

1H NMR (400 MHz, CDCl3): δ 7.50 (d, J=8.61 Hz, 2H), 7.13 (d, J=8.61 Hz,2H), 4.49 (s, 2H), 4.38-4.30 (m, 1H), 1.43 (d, J=6.65 Hz, 6H).

EXAMPLE 4

Following a procedure analogous to that described in Example 3, thefollowing compounds were prepared.

4A: 1-(4-Bromobenzyl)-3-cyclopropylimidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.50 (d, J=8.61 Hz, 2H), 7.14 (d, J=8.61 Hz,2H), 4.48 (s, 2H), 3.66 (s, 2H), 2.65-2.56 (m, 1H), 0.97 (d, J=5.87 Hz,4H).

4B: 1-(4-Bromobenzyl)-3-cyclobutylimidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.49 (d, J=8.22 Hz, 2H), 7.14 (d, J=8.22 Hz,2H), 4.60-4.51 (m, 1H), 4.49 (s, 2H), 3.65 (s, 2H), 2.95-2.82 (m, 2H),2.23-2.13 (m, 2H), 1.91-1.81 (m, 1H), 1.79-1.65 (m, 1H).

4C: 1-(4-Bromobenzyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.52 (d, J=8.61 Hz, 2H), 7.15 (d, J=8.61 Hz,2H), 4.55 (s, 2H), 4.16 (q, J=8.61 Hz, 2H), 3.83 (s, 2H).

4D: 1-(4-Bromobenzyl)-3-(1-cyclopropylethyl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.54 (d, J=8.61 Hz, 2H), 7.20 (d, J=8.61 Hz,2H), 4.72 (s, 2H), 3.87 (s, 2H), 3.46-3.36 (m, 1H), 1.22 (d, J=6.65 Hz,3H), 0.85-0.79 (m, 1H), 0.59-0.43 (m, 2H), 0.38-0.21 (m, 2H).

4E:(S)-1-(4-bromobenzyl)-3-(1-methoxypropan-2-yl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.49 (d, J=8.61 Hz, 2H), 7.13 (d, J=8.61 Hz,2H), 4.50 (d, J=3.91 Hz, 2H), 4.46-4.39 (m, 1H), 3.69 (s, 2H), 3.34 (s,3H), 1.18 (d, J=7.04 Hz, 3H).

4F: 1-(4-Bromobenzyl)-3-(tetrahydrofuran-3-yl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.50 (d, J=8.61 Hz, 2H), 7.14 (d, J=8.61 Hz,2H), 4.78-4.69 (m, 1H), 4.50 (s, 2H), 4.19-4.11 (m, 1H), 4.03-3.84 (m,3H), 3.70 (s, 2H), 2.41-2.32 (m, 1H), 2.26-2.14 (m, 1H).

4G: 1-(4-Bromobenzyl)-3-(oxazol-5-ylmethyl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.50 (d, J=8.61 Hz, 2H),7.15-7.11 (m, 3H), 4.77 (s, 2H), 4.52 (s, 2H), 3.77 (s, 2H).

EXAMPLE 5 2-Bromo-6-(piperidin-1-ylmethyl)pyridine

i) To a solution of 6-bromopyridine-2-carbaldehyde (25 g, 135 mmol) indichloromethane (500 ml) was slowly added piperidine (12.6 g, 149 mmol)at 10° C. After stirring for 15 minutes at 10° C., acetic acid (8.9 g,149 mmol) was added, followed by the portionwise addition of sodiumtriacetoxyborohydride, while the temperature was kept at 5-10° C. Afterstirring for 2 h at room temperature the reaction mixture was pouredinto a saturated aqueous solution of sodium hydrogen carbonate. Theproduct was extracted into dichloromethane and the combined organicphases were washed with brine, dried over sodium sulphate andconcentrated under reduced pressure. Column chromatography afforded2-bromo-6-(piperidin-1-ylmethyl)pyridine (30 g) as a colourless oil.

1H NMR (400 MHz, CDCl3): δ 7.54-7.43 (m, 2H), 7.33 (d, J=7.43 Hz, 1H),3.60 (s, 2H), 2.48-2.38 (m, 4H), 1.63-1.54 (m, 4H), 1.48-1.39 (m, 2H).

EXAMPLE 6

Following a procedure analogous to that described in Example 5, thefollowing compounds were prepared.

6A: 4-((6-Bromopyridin-2-yl)methyl)thiomorpholine 1,1-dioxide

1H NMR (400 MHz, CDCl3): δ 7.61-7.54 (dd, J=7.83 and 7.43 Hz, 1H), 7.42(d, J=7.83 Hz, 1H), 7.39 (d, J=7.43 Hz, 1H), 3.81 (s, 2H), 3.14-3.04 (m,8H).

6B: 4-((6-Bromopyridin-2-yl)methyl)morpholine

1H NMR (400 MHz, CDCl3): δ 7.53 (dd, J=7.83 and 7.43 Hz, 1H), 7.45 (d,J=7.83 Hz, 1H), 7.37 (d, J=7.43 Hz, 1H), 3.76-3.71 (m, 4H), 3.65 (s,2H), 2.55-2.49 (m, 4H).

6C: 2-Bromo-6-((3-methylpiperidin-1-yl)methyl)pyridine

1H NMR (400 MHz, CDCl3): δ 7.47-7.37 (m, 2H), 7.26 (d, J=7.43 Hz, 1H),3.54 (s, 2H), 2.76-2.64 (m, 2H), 1.92 (td, J=10.96 and 3.52 Hz, 1H),1.68-1.44 (m, 5H), 0.87-0.72 (m, 4H).

6D: 2-Bromo-6-((3,3-difluoropiperidin-1-yl)methyl)pyridine

1H NMR (400 MHz, CDCl3): δ 7.58-7.49 (m, 2H), 7.47 (d, J=7.43 Hz, 1H),3.74 (s, 2H), 2.71 (dd, J=11.35 and 10.96 Hz, 2H), 2.54 (dd, J=5.48 and5.09 Hz, 2H), 1.97-1.84 (m, 2H), 1.83-1.76 (m, 2H).

6E: 2-Bromo-6-((3-fluoropiperidin-1-yl)methyl)pyridine

1H NMR (400 MHz, CDCl3): δ 7.53 (dd, J=7.83 and 7.43 Hz, 1H), 7.47 (d,J=7.43 Hz, 1H), 7.36 (d, J=7.83 Hz, 1H), 4.76-4.56 (m, 1H), 3.68 (s,2H), 2.82-2.71 (m, 1H), 2.60-2.47 (m, 2H), 2.43-2.36 (m, 1H), 1.93-1.78(m, 2H), 1.73-1.50 (m, 2H).

6F: 2-Bromo-6-((3-trifluoromethylpiperidin-1-yl)methyl)pyridine

(m/z)=324 (M+H)+

6G: 1-((6-Bromopyridin-2-yl)methyl)-piperidin-3-one

1H NMR (400 MHz, CDCl3): δ 7.54 (dd, J=7.83 and 7.43 Hz, 1H), 7.41 (d,J=7.43 Hz, 1H), 7.38 (d, J=7.83 Hz, 1H), 3.73 (s, 2H), 3.08 (s, 2H),2.73 (dd, J=5.48 Hz, 2H), 2.39 (dd, J=7.04 Hz, 2H), 2.03-1.94 (m, 2H).

6H: N-((6-bromopyridin-2-yl)methyl)tetrahydro-2H-pyran-4-amine

1H NMR (400 MHz, CDCl3): δ 7.52 (dd, J=7.83 and 7.43 Hz, 1H), 7.37 (d,J=7.83 Hz, 1H), 7.31 (d, J=7.43 Hz, 1H), 4.02-3.96 (m, 2H), 3.93 (s,2H), 3.39 (td, J=11.74 and 2.35 Hz, 2H), 2.78-2.69 (m, 1H), 1.90-1.82(m, 2H), 1.55-1.42 (m, 2H).

6I: ((6-Bromopyridin-2-yl)methyl)cyclohexylamine

1H NMR (400 MHz, CDCl3): δ 7.50 (dd, J=7.83 and 7.43 Hz, 1H), 7.34 (d,J=7.83 Hz, 1H), 7.31 (d, J=7.43 Hz, 1H), 3.90 (s, 2H), 2.50-2.41 (m,1H), 1.96-1.88 (m, 2H), 1.78-1.69 (m, 3H), 1.65-1.57 (m, 1H), 1.31-1.06(m, 5H).

6J: N-((6-bromopyridin-2-yl)methyl)tetrahydro-2H-pyran-3-amine

1H NMR (400 MHz, CDCl3): δ 7.51 (dd, J=7.83 and 7.43 Hz, 1H), 7.36 (d,J=7.83 Hz, 1H), 7.31 (d, J=7.43 Hz, 1H), 3.96-3.89 (m, 3H), 3.83 (m,1H), 3.47-3.39 (m, 1H), 3.27-3.20 (dd, J=8.61 and 8.22 Hz, 1H),2.71-2.63 (m, 1H), 2.04-1.96 (m, 1H), 1.76-1.43 (m, 3H), 1.48-1.37 (m,1H).

6K: 4-((6-Bromopyridin-2-yl)methyl)thiomorpholine

1H NMR (400 MHz, CDCl3): δ 7.53 (dd, J=7.83 and 7.43 Hz, 1H), 7.42 (d,J=7.83 Hz, 1H), 7.37 (d, J=7.43 Hz, 1H), 3.67 (s, 2H), 2.84-2.66 (m,8H).

EXAMPLE 7

Following a procedure analogous to that described in Example 5 using6-bromo-3-fluoropyridine-2-carbaldehyde as the starting material, thefollowing compounds were prepared.

7A: 4-((6-Bromo-3-fluoropyridin-2-yl)methyl)thiomorpholine 1,1-dioxide

1H NMR (400 MHz, CDCl3): δ 7.45 (dd, J=8.22 and 3.52 Hz, 1H), 7.32 (d,J=8.61 and 8.22 Hz, 1H), 3.89 (d, J=2.74 Hz, 2H), 3.17 (m, 8H).

7B: 4-((6-Bromo-3-fluoropyridin-2-yl)methyl)morpholine

1H NMR (400 MHz, CDCl3): δ 7.41 (dd, J=8.22 and 3.52 Hz, 1H), 7.28 (d,J=8.61 and 8.22 Hz, 1H), 3.73-3.69 (m, 6H), 2.61-2.54 (m, 4H).

7C: 6-Bromo-3-fluoro-2-((3-methylpiperidin-1-yl)methyl)pyridine

(m/z)=288 (M+H)+

7D: 6-Bromo-3-fluoro-2-(piperidin-1-ylmethyl)pyridine

1H NMR (400 MHz, CDCl3): δ 7.38 (dd, J=8.22 and 3.52 Hz, 1H), 7.26 (d,J=8.61 and 8.22 Hz, 1H), 3.69 (d, J=2.74 Hz, 2H), 2.54-2.46 (m, 4H),1.61-1.53 (m, 4H), 1.45-1.36 (m, 2H).

7E: 6-Bromo-2-((3,3-dimethylpiperidin-1-yl)methyl)-3-fluoropyridine

1H NMR (400 MHz, CDCl3): δ 7.37 (dd, J=8.22 and 3.52 Hz, 1H), 7.25 (d,J=8.61 and 8.22 Hz, 1H), 3.66 (d, J=2.35 Hz, 2H), 2.41 (bs, 2H), 2.10(bs, 2H), 1.60-1.53 (m, 2H), 1.22-1.13 (m, 2H), 0.90 (s, 6H).

7F: 6-Bromo-2-((3,3-difluoropiperidin-1-yl)methyl)-3-fluoropyridine

1H NMR (400 MHz, CDCl3): δ 7.41 (dd, J=8.22 and 3.52 Hz, 1H), 7.29 (d,J=8.61 and 8.22 Hz, 1H), 3.86 (d, J=2.35 Hz, 2H), 2.79 (dd, J=11.35 and10.95 Hz, 2H), 2.59 (dd, J=5.48 and 5.09 Hz, 2H), 1.91-1.72 (m, 4H).

7G: 6-Bromo-3-fluoro-2-((3-fluoropiperidin-1-yl)methyl)pyridine

1H NMR (400 MHz, CDCl3): δ 7.40 (dd, J=8.61 and 3.52 Hz, 1H), 7.28 (d,J=8.61 and 8.22 Hz, 1H), 4.72-4.53 (m, 1H), 3.78 (bs, 2H), 2.97-2.86 (m,1H), 2.60-2.57 (m, 1H), 2.55-2.47 (m, 1H), 2.42-2.35 (m, 1H), 1.92-1.75(m, 2H), 1.62-1.47 (m, 2H).

7H: 6-Bromo-3-fluoro-2-((3-trifluoromethylpiperidin-1-yl)methyl)pyridine

(m/z)=342 (M+H)+

7I: N-((6-bromo-3-fluoropyridin-2-yl)methyl)tetrahydro-2H-pyran-4-amine

1H NMR (400 MHz, CDCl3): δ 7.37 (dd, J=8.61 and 3.52 Hz, 1H), 7.26 (d,J=8.61 and 8.22 Hz, 1H), 4.04-3.95 (m, 4H), 3.40 (td, J=11.73 and 1.96Hz, 2H), 2.76-2.66 (m, 1H), 1.90-1.81 (m, 2H), 1.56-1.42 (m, 2H).

7J: N-((6-bromo-3-fluoropyridin-2-yl)methyl)cyclohexanamine

1H NMR (400 MHz, CDCl3): δ 7.35 (dd, J=8.61 and 3.52 Hz, 1H), 7.24 (d,J=8.61 and 8.22 Hz, 1H), 3.96 (d, J=2.35 Hz, 2H), 2.50-2.40 (m, 1H),1.98-1.85 (m, 3H), 1.79-1.70 (m, 2H), 1.65-1.58 (m, 1H), 1.32-1.09 (m,5H).

7K: 1-((6-bromo-3-fluoropyridin-2-yl)methyl)piperidine-3-carbonitrile

1H NMR (400 MHz, CDCl3): δ 7.41 (dd, J=8.61 and 3.52 Hz, 1H), 7.29 (d,J=8.61 and 8.22 Hz, 1H), 3.77 (d, J=2.35 Hz, 2H), 2.96-2.87 (m, 1H),2.82-2.72 (m, 1H), 2.71-2.63 (m, 1H), 2.62-2.53 (m, 1H), 2.46-2.36 (m,1H), 1.93-1.71 (m, 2H), 1.64-1.52 (m, 2H).

7L: 4-((6-Bromo-3-fluoropyridin-2-yl)methyl)thiomorpholine

1H NMR (400 MHz, CDCl3): δ 7.40 (dd, J=8.61 and 3.52 Hz, 1H), 7.32 (d,J=8.61 and 8.22 Hz, 1H), 3.75 (d, J=2.74 Hz, 2H), 2.87-2.81 (m, 4H),2.71-2.65 (m, 4H).

EXAMPLE 8

Following a procedure analogous to that described in Example 5 using2-bromo-pyridine-4-carbaldehyde as the starting material, the followingcompound was prepared.

2-bromo-4-(piperidin-1-ylmethyl)pyridine

1H NMR (400 MHz, CDCl3): δ 8.27 (d, J=5.09, 1H), 7.48 (s, 1H), 7.23 (d,J=5.09 Hz, 1H), 3.93 (s, 2H), 2.41-2.31 (m, 4H), 1.63-1.55 (m, 4H),1.50-1.39 (m, 2H).

EXAMPLE 96-bromo-3-fluoro-2-((tetrahydro-2H-pyran-4-yloxy)methyl)pyridine

i) To a solution of 6-bromo-3-fluoro-2-methylpyridine (0.5 gr, 2.63mmol) in dichloromethane (5 ml) were added at room temperatureN-bromosuccinimide (937 mg, 5.26 mmol) and azo-di-isobutyronitrile (86mg, 0.526 mmol). After 17 h stirring at 55° C. the reaction mixture wasquenched by the addition of water and the product was extracted intodichloromethane. The combined organic phases were washed with brine,dried over sodium sulfate and concentrated under reduced pressure.Column chromatography afforded 6-bromo-2-(bromomethyl)-3-fluoropyridine(388 mg) as a clear oil.

ii) To a solution of the product obtained in the previous step (388 mg,1.44 mmol) and tetrahydro-2H-pyran-4-ol (0.206 ml, 2.16 mmol) intetrahydrofuran (10 ml) was added sodium hydride (69.3 mg, 2.31 mmol,80% dispersion in oil). After 1 h stirring at room temperature thereaction mixture was quenched by the addition of water and the productwas extracted into dichloromethane. The combined organic phases werewashed with brine, dried over sodium sulfate and concentrated underreduced pressure. Column chromatography afforded the title compound6-bromo-3-fluoro-2-((tetrahydro-2H-pyran-4-yloxy)methyl)pyridine (177mg) as a clear oil.

1H NMR (400 MHz, CDCl3): δ 7.44 (dd, J=8.61 and 3.52 Hz, 1H), 7.31 (d,J=8.61 and 8.22 Hz, 1H), 4.67 (d, J=2.35 Hz, 2H), 3.99-3.92 (m, 2H),3.72-3.64 (m, 1H), 3.49-3.41 (m, 2H), 2.00-1.91 (m, 2H), 1.71-1.60 (m,2H).

EXAMPLE 10 2-Bromo-6-(cyclohexylmethyl)pyridine

i) A solution of 2,6-dibromopyridine (1.37 g, 5.8 mmol) inTHF/hexane/diethyl ether (1/1/3, 15 ml) was added dropwise, under anitrogen atmosphere, to a solution of a 2.5 M n-butyllithium in hexane(2.43 ml, 6.08 mmol) at −78° C.

After 10 minutes stirring, a solution of cyclohexanecarbonitrile (633mg, 5.8 mmol) in THF/hexane/diethyl ether (1/1/3, 4 ml) was added andthe reaction mixture was stirred for 2.5 h at −78° C. The reactionmixture was warmed to room temperature and stirred for another 1.5 h.The reaction mixture was quenched by the addition of an aqueous solutionof 2M sulfuric acid (7 ml). after vigorous stirring for 2 h, water wasadded and the product was extracted into diethyl ether. The combinedorganic phases were washed with a saturated aqueous solution of sodiumhydrogen carbonate, brine, dried over sodium sulfate and concentratedunder reduced pressure. Column chromatography afforded(6-bromo-pyridin-2-yl)(cyclohexyl)methanone (800 mg) as a clear oil.

ii) A suspension of the product obtained in the previous step (600 mg,2.24 mmol) and 4-methylbenzenesulfonyl hydrazide (458 mg, 2.46 mmol) inethanol (2 ml) was heated to 100° C. for 15 minutes, in a microwave.After cooling to room temperature the reaction mixture concentratedunder reduced pressure. Column chromatography affordedN′-((6-bromopyridin-2-yl)(cyclohexyl)methylene)-4-methylbenzenesulfonohydrazide(608 mg) as a white solid.

iii) To a solution of the product obtained in the previous step (600 mg,1.38 mmol) in 4 ml dichloromethane was added slowly to a solution of 20%diisobutylaluminiumhydride in toluene (0.97 g, 13.8 mmol). After 17 hstirring at room temperature the reaction mixture was quenched by addingslowly an aqueous solution of 2M sodium hydroxide until pH=10. Theproduct was extracted into ethylacetate and the combined organic phaseswere washed with water, brine, dried over sodium sulfate andconcentrated under reduced pressure. Column chromatography afforded thetitle compound 2-bromo-6-(cyclohexylmethyl)pyridine as a white solid.

1H NMR (400 MHz, CDCl3): δ 7.42-7.21 (m, 3H), 3.62 (d, J=7.04 Hz, 2H),1.81-0.85 (m, 11H).

EXAMPLE 11 2-Bromo-6-(difluoro-(tetrahydro-2H-pyran-4-yl)methyl)pyridine

i) (6-Bromo-pyridin-2-yl)-(tetrahydro-2H-pyran-4-yl)methanone wasprepared following a procedure analogous to that described in Example10, step i), using tetrahydro-2H-pyran-4-carbonitrile as the startingmaterial.

ii) To a solution of the product obtained in the previous step (200 mg,0.74 mmol) in dichloromethane (2 ml) was added portionwise, over aperiod of 6 days, di-ethylaminosulfur-tri-fluoride (1.49 g, 9.25 mmol),under a nitrogen atmosphere. After completion the reaction mixture wasquenched carefully by addition of methanol and the product was extractedinto ethylacetate. The combined organic phases were washed with water,brine, dried over sodium sulfate and concentrated under reducedpressure. Column chromatography afforded the title compound2-bromo-6-(difluoro-(tetrahydro-2H-pyran-4-yl)methyl)pyridine (144 mg)as a clear oil.

1H NMR (400 MHz, CDCl3): δ 7670 (t, J=7.83 Hz, 1H), 7.60-7.54 (m, 3H),4.03 (dd, J=11.35 and 4.30 Hz, 2H), 3.42 (td, J=11.74 and 2.35 Hz, 2H),2.80-2.63 (m, 1H), 1.72 (m, 4H).

EXAMPLE 123-Isobutyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione

i) To a solution of 1-(4-bromobenzyl)-3-isobutylimidazolidine-2,4-dione(Example 1, step i)) (2.0 g, 6.2 mmol), bis(pinacolato)diboron 1.6 g,6.2 mmol) and potassium acetate (1.8 g, 18.5 mmol) in DMF (50 ml) undera nitrogen atmosphere was added1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) (134 mg, 0.18mmol). After 17 h stirring at 75° C. the reaction mixture was cooled toroom temperature. Water was added and the product was extracted intoethylacetate. The combined organic phases were washed with a saturatedaqueous solution of sodium hydrogen carbonate, water, brine, dried oversodium sulfate and concentrated under reduced pressure to afford3-Isobutyl-1-(4-(4,4,5,5-tetramethyl-(1,3,2)dioxaborolan-2-yl)benzyl)imidazolidine-2,4-dione(6.8 g) as a black oil. The product was used in the following stepwithout further purification.

ii) To a solution of the product obtained in the previous step (1.31 g,3.52 mmol) and 2-bromo-6-(piperidin-1-ylmethyl)pyridine (example 5) (748mg, 2.93 mmol) in toluene/ethanol (4/1, 25 ml) was added an aqueoussolution of 2M potassium carbonate. After 15 minutes stirring under anitrogen atmosphere, tetrakis(triphenylphosphine)palladium(0) (85 mg,0.073 mmol) was added and this mixture was stirred for 17 h at 75° C.under a nitrogen atmosphere. After completion, the mixture was cooled toroom temperature and filtered through decalite. Water was added to thefiltrate and the product was extracted into ethylacetate. The combinedorganic phases were washed with water, brine, dried over sodium sulfateand concentrated under reduced pressure. Column chromatography afforded3-Isobutyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione(120 mg) as a white solid.

1H NMR (400 MHz, CDCl3): δ 8.00 (d, J=8.22 Hz, 2H), 7.72 (dd, J=8.22 and7.83 Hz, 1H), 7.56 (d, J=8.22 Hz, 1H), 7.43 (d, J=7.83 Hz, 1H), 7.34 (d,J=8.22 Hz, 2H), 4.62 (s, 2H), 3.74 (s, 2H), 3.72 (s, 2H), 3.36 (d,J=7.43 Hz, 2H), 2.53-2.47 (m, 4H), 1.65-1.58 (m, 4H), 1.50-1.42 (m, 2H),2.15-2.05 (m, 1H), 0.93 (d, J=6.65 Hz, 6H).

Following a procedure analogous to that described in Example 12 thefollowing compounds were prepared:

Starting Examples materials 133-isobutyl-1-(4-(6-(morpholinomethyl)pyridin-2- 1, 6Byl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.99 (d, J= 8.61 Hz, 2H), 7.62 (dd, J = 7.83 and 7.43 Hz, 1H), 7.59 (d, J = 7.83Hz, 1H), 7.43 (d, J = 7.43 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.62 (s,2H), 3.76 (s, 2H), 3.75 (s, 2H), 3.37 (d, J = 7.43 Hz, 2H), 2.61-2.56(m, 4H), 2.14- 2.05 (m, 1H), 1.59-1.53 (m, 4H), 0.93 (d, J = 6.65 Hz,6H). 14 1-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-1, 7I 2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione ¹H NMR (400 MHz,CDCl₃): δ 7.95 (d, J = 8.61 Hz, 2H), 7.62 (dd, J = 8.61 and 3.52 Hz,1H), 7.43 (dd, J = 9.00 and 8.61 Hz, 1H), 7.35 (d, J = 8.61 Hz, 2H),4.63 (s, 2H), 4.08 (s, 2H), 4.04-3.97 (m, 2H), 3.76 (s, 2H), 3.49 (d, J= 3.13 Hz, 1H), 3.42 (td, J = 11.7 and 2.35 Hz, 2H), 3.37 (d, J = 7.43Hz, 2H), 2.83-2.73 (m, 1H), 2.17-2.04 (m, 1H), 1.95-1.87 (m, 2H),1.62-1.47 (m, 1H), 0.93 (d, J = 6.65 Hz, 6H). 151-(4-(6-((1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)methyl)pyridin-2- 1, 6Ayl)benzyl)-3-isobutylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.98 (d, J = 8.61 Hz, 2H), 7.77 (dd, J = 7.83 and 7.43 Hz, 1H), 7.63 (d,J = 7.83 Hz, 1H), 7.36 (m, 3H), 4.63 (s, 2H), 3.92 (s, 2H), 3.76 (s,2H), 3.37 (d, J = 7.43 Hz, 2H), 3.18-3.09 (m, 8H), 2.15-2.04 (m, 1H),0.93 (d, J = 6.65 Hz, 6H). 161-(4-(6-((1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)methyl)-5-fluoropyridin- 1, 7A 2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione ¹H NMR (400 MHz,CDCl₃): δ 7.94 (d, J = 8.22 Hz, 2H), 7.68 (dd, J = 8.61 and 3.52 Hz,1H), 7.48 (dd, J = 9.00 and 8.61 Hz, 1H), 7.36 (d, J = 8.22 Hz, 2H),4.62 (s, 2H), 4.02 (d, J = 2.35 Hz, 2H), 3.76 (s, 2H), 3.37 (s, 2H),3.24-3.18 (m, 4H), 3.13-3.06 (m, 4H), 2.14-2.04 (m, 1H), 0.93 (d, J =7.04 Hz, 6H). 171-(4-(5-Fluoro-6-((3-methylpiperidin-1-yl)methyl)pyridin-2- 1, 7Cyl)benzyl)-3-isobutylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.96 (d, J = 8.22 Hz, 2H), 7.62 (dd, J = 8.61 and 3.52 Hz, 1H), 7.43(dd, J = 9.00 and 8.61 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H), 4.62 (s, 2H),3.83 (bs, 2H), 3.76 (s, 2H), 3.37 (d, J = 7.43 Hz, 2H), 3.06-2.94 (m,2H), 2.15-2.02 (m, 2H), 1.81-1.55 (m, 6H), 0.93 (d, J = 7.04 Hz, 6H),0.85 (d, J = 5.87 Hz, 3H). 181-(4-(6-((3,3-Difluoro-piperidin-1-yl)methyl)-5-fluoro-pyridin-2- 1, 7Fyl)benzyl)-3-isobutylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.96 (d, J = 8.22 Hz, 2H), 7.66 (dd, J = 8.61 and 3.52 Hz, 1H), 7.46(dd, J = 1, 9.00 and 8.61 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.62 (s,2H), 3.99 (d, J = 2.35 Hz, 2H), 3.76 (s, 2H), 3.37 (d, J = 7.43 Hz, 2H),2.88 (t, J = 11.35 Hz, 2H), 2.69-2.62 (m, 2H), 2.17-2.05 (m, 1H),1.92-1.74 (m, 4H), 0.93 (d, J = 6.65 Hz, 6H). 191-(4-(5-Fluoro-6-((3-fluoro-piperidin-1-yl)methyl)pyridin-2- 1, 7Gyl)benzyl)-3-isobutylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.96 (d, J = 8.22 Hz, 2H), 7.64 (dd, J = 8.61 and 3.52 Hz, 1H), 7.44 (d,J = 9.00 and 8.61 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.62 (s, 2H), 3.86(d, J = 2.35 Hz, 2H), 3.76 (s, 2H), 3.37 (d, J = 7.43 Hz, 2H), 2.84-2.75(m, 2H), 2.64- 2.54 (m, 2H), 2.17-1.85 (m, 6H), 0.93 (d, J = 6.65 Hz,6H). 201-(4-(5-Fluoro-6-((3-trifluoromethyl-piperidin-1-yl)methyl)pyridin-2- 1,7H yl)benzyl)-3-isobutylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃):δ 7.94 (d, J = 8.22 Hz, 2H), 7.64 (dd, J = 8.61 and 3.52 Hz, 1H), 7.45(dd, J = 9.00 and 8.61 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H), 4.62 (s, 2H),3.88 (bs, 2H), 3.76 (s, 2H), 3.37 (d, J = 7.04 Hz, 2H), 3.32-3.25 (m,1H), 3.09-3.01 (m, 1H), 2.46-2.34 (m, 1H), 2.23-2.04 (m, 3H), 1.98-1.88(m, 1H), 1.79- 1.68 (m, 1H), 1.31-1.21 (m, 2H), 0.93 (d, J = 6.65 Hz,6H). 211-(4-(6-((Cyclohexyl)amino)methyl-5-fluoro-pyridin-2-yl)benzyl)-3- 1, 7Jisobutylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, J =8.22 Hz, 2H), 7.60 (dd, J = 8.61 and 3.52 Hz, 1H), 7.41 (dd, J = 9.00and 8.61 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.62 (s, 2H), 4.07 (d, J =1.96 Hz, 2H), 3.77 (s, 2H), 3.37 (d, J = 7.43 Hz, 2H), 2.57-2.47 (m,1H), 2.16- 2.04 (m, 1H), 2.02-1.94 (m, 2H), 1.81-1.72 (m, 2H), 1.67-1.59(m, 1H), 1.33-1.13 (m, 5H), 0.93 (d, J = 6.65 Hz, 6H). 223-Isobutyl-1-(4-(6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin- 1, 6H2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 8.00 (d,J = 8.61 Hz, 2H), 7.72 (dd, J = 7.83 and 7.43 Hz, 1H), 7.59 (d, J = 7.83Hz, 1H) 7.36 (d, J = 8.61 Hz, 2H), 7.26 (d, J = 7.43, 1H) 4.63 (s, 2H),4.04-3.96 (m, 4H), 3.76 (s, 2H), 3.42 (Td, 11.74 and 1.96 Hz, 2H), 3.83(d, J = 2.74 Hz, 2H), 2.62-2.53 (m, 4H), 2.25 (s, 3H), 1.65-1.55 (m,4H), 1.47-1.38 (m, 2H). 231-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-yloxy)methyl)pyridin-2- 1, 9yl)benzyl)-3-isobutylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.96 (d, J = 8.22 Hz, 2H), 7.68 (dd, J = 8.61 and 3.52 Hz, 1H), 7.47 (d,J = 9.00 and 8.61 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H), 4.79 (d, J = 1.96Hz, 2H), 4.62 (s, 2H), 4.01-3.77 (m, 2H), 3.79-3.70 (m, 3H), 3.50-3.41(m, 2H), 3.37 (d, J = 7.43 Hz, 2H), 2.15-2.05 (m, 1H), 2.04-1.95 (m,2H), 1.76- 1.62 (m, 2H), 0.93 (d, J = 6.65 Hz, 6H). 241-(4-(5-Fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3- 2A, 7Dmethylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, J =8.22 Hz, 2H), 7.62 (dd, J = 8.61 and 3.52 Hz, 1H), 7.42 (dd, J = 9.00and 8.61 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.62 (s, 2H), 3.82 (d, J =2.35 Hz, 2H), 3.76 (s, 2H), 3.07 (s, 3H), 2.61-2.54 (m, 4H), 1.64-1.57(m, 4H), 1.45-1.37 (m, 2H). 253-ethyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2- 2B, 5yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.99 (d, J= 8.22 Hz, 2H), 7.74 (dd, J = 7.83 and 7.43 Hz, 1H), 7.61 (d, J = 7.83Hz, 1H), 7.45 (d, J = 7.43 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.61 (s,2H), 3.72 (bs, 4H), 3.61 (q, J = 7.04 Hz, 2H), 2.53-2.47 (m, 4H),1.65-1.57 (m, 4H), 1.50-1.43 (m, 2H), 1.25 (t, 3H). 263-ethyl-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2- 2B, 7Dyl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.97 (d, J= 8.22 Hz, 2H), 7.63 (dd, J = 8.61 and 3.52 Hz, 1H), 7.43 (dd, J = 9.00and 8.61 Hz, 1H), 7.35 (d, J = 8.61 Hz, 2H), 4.61 (s, 2H), 3.85 (d, J =2.35 Hz, 2H), 3.74 (s, 2H), 3.61 (q, J = 7.43 Hz, 2H), 2.62 (bs, 4H),1.66-1.57 (m, 4H), 1.47-1.38 (m, 2H), 1.25 (t, J = 7.43, 3H). 271-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2- 2B,7A yl)benzyl)-3-ethylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.94 (d, J = 8.22 Hz, 2H), 7.69 (dd, J = 8.61 and 3.52 Hz, 1H), 7.49(dd, J = 9.00 and 8.61 Hz, 1H), 7.36 (d, J = 8.22 Hz, 2H), 4.62 (s, 2H),4.02 (d, J = 2.35 Hz, 2H), 3.75 (s, 2H), 3.60 (q, J = 7.43 Hz, 2H),3.26-3.17 (m, 4H), 3.14- 3.04 (m, 4H), 1.25 (t, J = 7.43, 3H). 281-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)pyridin-2- 2B, 6Ayl)benzyl)-3-ethylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.98 (d, J = 8.22 Hz, 2H), 7.77 (dd, J = 7.83 and 7.43 Hz, 1H), 7.63 (d,J = 7.83 Hz, 1H), 7.39-7.34 (m, 2H), 4.62 (s, 2H), 3.93 (s, 2H), 3.73(s, 2H), 3.61 (q, J = 7.04 Hz, 2H), 3.19-3.08 (m, 8H), 1.25 (t, J =7.04, 3H). 291-((6-(4-((3-ethyl-2,4-dioxoimidazolidin-1-yl)methyl)phenyl)-3- 2B, 7Kfluoropyridin-2-yl)methyl)piperidine-3-carbonitrile ¹H NMR (400 MHz,CDCl₃): δ 7.96 (d, J = 8.22 Hz, 2H), 7.65 (dd, J = 8.61 and 3.52 Hz,1H), 7.45 (dd, J = 9.00 and 8.61 Hz, 1H), 7.36 (d, J = 8.22 Hz, 1H),4.62 (s, 2H), 3.90 (d, J = 2.35 Hz, 2H), 3.74 (s, 2H), 3.61 (q, J = 7.04Hz, 2H), 3.03-2.95 (m, 1H), 2.84- 2.72 (m, 2H), 2.71-2.65 (m, 1H),2.55-2.46 (m, 1H), 1.94-1.76 (m., 2H), 1.70-1.58 (m, 2H), 1.25 (t, J =7.04 Hz, 3H). 30 1-(4-(6-(cyclohexylmethyl)pyridin-2-yl)benzyl)-3- 2B,10 ethylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.99 (d, J =8.22 Hz, 2H), 7.64 (dd, J = 7.83 and 7.43 Hz, 1H), 7.50 (d, J = 7.83 Hz,1H), 7.35 (d, J = 8.22 Hz, 2H), 7.05 (d, J = 7.43 Hz, 1H), 4.62 (s, 2H),3.73 (s, 2H), 3.61 (q, J = 7.43 Hz, 2H), 2.72 (d, J = 7.04 Hz, 2H),1.92-1.78 (m, 1H), 1.76-1.58 (m, 6H), 1.31-1.15 (m, 5H), 1.10-0.98 (m,2H). 31 1-(4-(5-Fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-2C, 7D propylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d,J = 8.61 Hz, 2H), 7.63 (dd, J = 8.61 and 3.52 Hz, 1H), 7.43 (dd, J =9.00 and 8.61 Hz, 1H), 7.34 (d, J = 8.61 Hz, 2H), 4.61 (s, 2H), 3.74 (s,2H), 3.51 (t, J = 7.04 Hz, 2H), 3.49 (s, 2H), 2.70-2.51 (m, 4H),1.76-1.55 (m, 6H), 1.49-1.35 (m, 2H), 0.94 (t, J = 7.04, 3H). 321-(4-(6-(Piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3- 2C, 5propylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.99 (d, J =8.22 Hz, 2H), 7.22 (dd, J = 7.83 and 7.04 Hz, 1H), 7.56 (d, J = 7.83 Hz,1H) 7.43 (d, J = 7.04 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H), 4.61 (s, 2H),3.73 (s, 2H), 3.71 (s, 2H), 3.51 (t, J = 7.43 Hz, 2H), 2.53-2.47 (m,4H), 1.73- 1.56 (m, 6H), 1.50-1.42 (m, 2H), 0.94 (t, J = 7.43, 3H). 333-Propyl-1-(4-(6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin- 2C, 6H2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 8.00 (d,J = 8.61 Hz, 2H), 7.72 (dd, J = 7.83 and 7.43 Hz, 1H), 7.59 (d, J = 7.83Hz, 1H), 7.36 (d, J = 8.61 Hz, 2H), 7.26 (d, J = 7.43, 1H) 4.62 (s, 2H),4.04-3.97 (m, 4H), 3.75 (s, 2H), 3.54-3.44 (m, 2H), 3.42 (Td, J = 11.35and 2.35 Hz, 2H), 2.84-2.74 (m, 1H), 1.94-1.87 (m, 2H), 1.74-1.62 (m,2H), 1.57-1.46 (m, 2H), 0.94 (t, J = 7.43 Hz, 3H). 341-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin- 2C, 7I2-yl)benzyl)-3-propylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.95 (d, J = 8.61 Hz, 2H), 7.61 (dd, J = 8.61 and 3.91 Hz, 1H), 7.43 (d,J = 9.00 and 8.61 Hz, 1H), 7.35 (d, J = 8.61 Hz, 2H), 4.62 (s, 2H), 4.08(d, J = 1.96 Hz, 2H), 4.04-3.98 (m, 2H), 3.75 (s, 2H), 3.54-3.48 (m,2H), 3.42 (Td, J = 11.74 and 2.35 Hz, 2H), 2.83-2.74 (m, 1H), 1.95-1.88(m, 2H), 1.73-1.63 (m, 2H), 1.56-1.49 (m, 2H), 0.95 (t, J = 7.43 Hz,3H). 351-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl-5-fluoropyridin-2- 2C,7A yl)benzyl)-3-propylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.94 (d, J = 8.22 Hz, 2H), 7.68 (dd, J = 8.61 and 3.91 Hz, 1H), 7.48 (d,J = 9.00 and 8.61 Hz, 1H), 7.36 (d, J = 8.22 Hz, 2H), 4.62 (s, 2H), 4.02(d, J = 2.35 Hz, 2H), 3.75 (s, 2H), 3.54-3.49 (m, 2H), 3.25-3.19 (m,4H), 3.13-3.07 (m, 4H), 1.73-1.64 (m, 2H), 0.95 (t, J = 7.43 Hz, 3H). 361-(4-(6-(1,1-Dioxo-1 λ⁶-thiomorpholin-4-ylmethyl)pyridin-2- 2C, 6Ayl)benzyl)-3-propylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.98 (d, J = 8.22 Hz, 2H), 7.77 (dd, J = 7.83 and 7.43 Hz, 1H), 7.63 (d,J = 7.83 Hz, 1H), 7.36 (m, 3H), 4.62 (s, 2H), 3.92 (s, 2H), 3.74 (s,2H), 3.54-3.48 (m, 2H), 3.18- 3.07 (m, 8H), 1.74-1.63 (m, 2H), 0.94 (t,J = 7.43 Hz, 3H). 373-propyl-1-(4-(6-((tetrahydro-2H-pyran-3-ylamino)methyl)pyridin-2- 2C,6J yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 8.00 (d,J = 8.22, 2H), 7.71 (dd, J = 8.22 and 7.43 Hz, 1H), 7.58 (d, J = 7.83Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 7.25 (d, J = 7.43 Hz, 1H), 4.62 (s,2H), 4.02-3.95 (m, 3H), 3.85-3.78 (m, 1H), 3.75 (s, 2H), 3.54-3.40 (m,3H), 3.27 (dd, J = 10.46 and 8.61 Hz, 1H), 2.79-2.70 (m, 1H), 2.09-1.94(m, 2H), 1.748-1.56 (m, 4H), 1.52-1.39 (m, 1H), 0.94 (t, J = 7.43 Hz,3H). 38 3-(2,2-Difluoroethyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-2D, 5 yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 8.00(d, J = 8.61 Hz, 2H), 7.73 (dd, J = 7.83 and 7.42 Hz, 1H), 7.56 (d, J =7.83 Hz, 1H), 7.44 (d, J = 7.43 Hz, 1H), 7.35 (d, J = 8.61 Hz, 2H), 6.05(Tt, J = 55.6 and 4.30 Hz, 1H), 4.63 (s, 2H), 3.92 (Td, J = 13.7 and4.30 Hz, 2H), 3.81 (s, 2H), 3.72 (s, 2H), 2.54-2.40 (m, 4H), 1.67-1.56(m, 4H), 1.50-1.41 (m, 2H). 393-(2,2-Difluoroethyl)-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2D, 7D 2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.98 (d, J = 8.61 Hz, 2H), 7.62 (dd, J = 8.61 and 3.52 Hz, 1H), 7.43(dd, J = 9.00 and 8.61 Hz, 1H), 7.37 (d, J = 8.61 Hz, 2H), 4.05 (Tt, J =55.95 and 4.30 Hz, 1H), 4.63 (s, 2H), 3.92 (Td, J = 13.69 and 4.30 Hz,2H), 3.83 (s, 2H), 3.82 (s, 2H), 2.63-2.55 (m, 4H), 1.65-1.55 (m, 4H),1.45-1.37 (m, 2H). 403-(Cyclopropylmethyl)-1-(4-(5-fluoro-6-(Piperidin-1- 2E, 7Dylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz,CDCl₃): δ 7.97 (d, J = 8.22 Hz, 2H), 7.62 (dd, J = 8.61 and 3.52 Hz,1H), 7.42 (t, J = 8.61 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.62 (s, 2H),3.82 (d, J = 2.74 Hz, 2H), 3.76 (s, 2H), 3.41 (d, J = 7.01 Hz, 2H),2.61-2.55 (m, 4H), 1.64-1.56 (m, 4H), 1.45-1.38 (m, 2H), 1.23-1.16 (m,1H), 0.55-0.48 (m, 2H), 0.39- 0.34 (m, 2H). 413-Cyclopropylmethyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2- 2E, 5yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.99 (d, J= 8.22 Hz, 2H), 7.72 (dd, J = 8.22 and 7.83 Hz, 1H), 7.56 (d, J = 8.22Hz, 1H), 7.43 (d, J = 7.83 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.62 (s,2H), 3.75 (s, 2H), 3.72 (s, 2H), 3.41 (d, J = 7.04 Hz, 2H), 2.53-2.47(m, 4H), 1.654- 1.58 (m, 4H), 1.52-1.42 (m, 2H), 1.24-1.14 (m, 1H),0.56-0.47 (m, 2H), 0.40-0.33 (m, 2H). 423-Cyclobutylmethyl-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2- 2F,7D yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d,J = 8.22 Hz, 2H), 7.62 (dd, J = 8.61 and 3.52 Hz, 1H), 7.42 (t, J = 8.61Hz, 1H), 7.33 (d, J = 8.22 Hz, 2H), 4.60 (s, 2H), 3.82 (d, J = 2.74 Hz,2H), 3.73 (s, 2H), 3.58 (d, J = 7.43 Hz, 2H), 2.76-2.66 (m, 1H),2.63-2.53 (m, 4H), 2.09-1.99 (m, 2H), 1.93-1.84 (m, 2H), 1.83-1.75 (m,2H), 1.64- 1.57 (m, 4H), 1.47-1.37 (m, 2H). 433-Cyclobutylmethyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2- 2F, 5yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, J= 8.22 Hz, 2H), 7.62 (dd, J = 8.22 and 7.83 Hz, 1H), 7.56 (d, J = 8.22Hz, 1H), 7.43 (d, J = 7.83 Hz, 1H), 7.33 (d, J = 8.22 Hz, 2H), 4.61 (s,2H), 3.72 (bs, 4H), 3.58 (d, J = 7.43 Hz, 2H), 2.76-2.66 (m, 1H),2.54-2.46 (m, 4H), 2.09-1.98 (m, 2H), 1.93-1.75 (m, 4H), 1.66-1.56 (m,4H), 1.51-1.41 (m, 2H). 443-(2-Methoxyethyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2- 2G, 5yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.99 (d, J= 8.22 Hz, 2H), 7.72 (dd, J = 7.83 and 7.43 Hz, 1H), 7.57 (d, J = 7.83Hz, 1H), 7.43 (d, J = 7.43 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.62 (s,2H), 3.78-3.73 (m, 6H), 3.61 (t, J = 5.48 Hz, 2H), 3.37 (s, 3H), 2.52(bs, 4H), 1.67- 1.59 (m, 4H), 1.51-1.43 (m, 2H). 451-(4-(5-Fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(2- 2G, 7Dmethoxy-ethyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.96(d, J = 8.22 Hz, 2H), 7.63 (dd, J = 8.61 and 3.53 Hz, 1H), 7.43 (dd, J =9.00 and 8.61 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.62 (s, 2H), 3.83 (s,2H), 3.78 (s, 2H), 3.76 (t, J = 5.48 Hz, 2H), 3.61 (t, J = 5.48 Hz, 2H),3.30 (s, 3H), 2.62-2.55 (m, 4H), 1.65-1.55 (m, 4H), 1.45-1.37 (m, 2H).46 (2,5-Dioxo-3-(4-(6-(piperidin-1-ylmethyl)pyridin-2- 2H, 5yl)benzyl)imidazolidin-1-yl)acetic acid methyl ester ¹H NMR (400 MHz,CDCl₃): δ 8.00 (d, J = 8.61 Hz, 2H), 7.72 (dd, J = 7.83 and 7.43 Hz,1H), 7.56 (d, J = 7.83 Hz, 1H), 7.43 (d, J = 7.43 Hz, 1H), 7.35 (d, J =8.61 Hz, 2H), 4.65 (s, 2H), 4.31 (s, 2H), 3.83 (s, 2H), 3.79 (s, 3H),3.72 (s, 2H), 2.54-2.47 (m, 4H), 1.65- 1.58 (m, 4H), 1.50-1.43 (m, 2H).47 (3-(4-(5-Fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-2,5- 2H,7D dioxo-imidazolidin-1-yl)acetic acid methyl ester ¹H NMR (400 MHz,CDCl₃): δ 7.97 (d, J = 8.22 Hz, 2H), 7.63 (dd, J = 8.61 and 3.52 Hz,1H), 7.43 (dd, J = 9.00 and 8.61 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H),4.65 (s, 2H), 4.32 (s, 2H), 3.85 (s, 4H), 3.79 (s, 3H), 2.67-2.56 (m,4H), 1.65-1.56 (m, 4H), 1.46-1.38 (m, 2H). 483-(2-Oxopropyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2- 2I, 5yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 8.00 (d, J= 8.22 Hz, 2H), 7.73 (dd, J = 7.83 and 7.43 Hz, 1H), 7.56 (d, J = 7.83Hz, 1H) 7.43 (d, J = 7.43 Hz, 1H), 7.36 (d, J = 8.22 Hz, 2H), 4.64 (s,2H), 4.36 (s, 2H), 3.85 (s, 2H), 3.72 (s, 2H), 2.54-2.46 (m, 4H), 2.25(s, 3H), 1.66- 1.58 (m, 4H), 1.50-1.42 (m, 2H). 491-(4-(5-Fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(2- 2I, 7Doxopropyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, J= 8.22 Hz, 2H), 7.62 (dd, J = 8.61 and 3.52 Hz, 1H), 7.43 (dd, J = 9.00and 8.61 Hz, 1H) 7.36 (d, J = 8.22 Hz, 1H), 4.64 (s, 2H), 4.37 (s, 2H),3.86 (s, 2H), 3.83 (d, J = 2.74 Hz, 2H), 2.62-2.53 (m, 4H), 2.25 (s,3H), 1.65- 1.55 (m, 4H), 1.47-1.38 (m, 2H). 501-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2- 2I,7A yl)benzyl)-3-(2-oxopropyl)imidazolidine-2,4-dione ¹H NMR (400 MHz,CDCl₃): δ 7.95 (d, J = 8.22 Hz, 2H), 7.68 (dd, J = 8.61 and 3.52 Hz,1H), 7.48 (d, J = 9.00 and 8.61 Hz, 1H), 7.37 (d, J = 8.22 Hz, 2H), 4.65(s, 2H), 4.37 (s, 2H), 4.02 (d, J = 2.74 Hz, 2H), 3.86 (s, 2H),3.24-3.19 (m, 4H), 3.13-3.07 (m, 4H), 2.26 (s, 3H). 513-(2-Oxo-propyl)-1-(4-(6-((tetrahydro-2H-pyran-4- 2I, 6Hylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400MHz, CDCl₃): δ 8.01 (d, J = 8.61 Hz, 2H), 7.72 (dd, J = 7.83 and 7.43Hz, 1H), 7.59 (d, J = 7.83 Hz, 1H), 7.37 (d, J = 8.61 Hz, 2H), 7.25 (d,J = 7.43 Hz, 1H), 4.65 (s, 2H), 4.37 (s, 2H), 4.05-3.97 (m, 4H), 3.86(s, 2H), 3.42 (Td, J = 11.74 and 2.35 Hz, 2H), 2.84-2.75 (m, 1H), 2.25(s, 3H), 1.94-1.87 (m, 2H), 1.58- 1.48 (m, 2H). 521-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin- 2I, 7I2-yl)benzyl)-3-(2-oxo-propyl)imidazolidine-2,4-dione ¹H NMR (400 MHz,CDCl₃): δ 7.97 (d, J = 8.22 Hz, 2H), 7.62 (dd, J = 8.61 and 3.52 Hz,1H), 7.43 (dd, J = 9.00 and 8.61 Hz, 1H), 7.37 (d, J = 8.22 Hz, 2H),4.65 (s, 2H), 4.37 (s, 2H), 4.08 (d, J = 2.75 Hz, 2H), 4.04-3.98 (m,2H), 3.87 (s, 2H), 3.42 (Td, J = 11.74 and 2.35 Hz, 2H), 2.83-2.74 (m,1H), 2.25 (s, 3H), 1.95-1.88 (m, 2H), 1.56-1.49 (m, 2H). 531-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)pyridin-2- 2I, 6^(a)yl)benzyl)-3-(2-oxo-propyl)imidazolidine-2,4-dione ¹H NMR (400 MHz,CDCl₃): δ 8.00 (d, J = 8.22 Hz, 2H), 7.77 (dd, J = 7.83 and 7.43 Hz,1H), 7.64 (d, J = 7.83 Hz, 1H), 7.41-7.33 (m, 3H), 4.65 (s, 2H), 4.36(s, 2H), 3.92 (s, 2H), 3.85 (s, 2H), 3.19- 3.08 (m, 8H), 2.26 (s, 3H).54 1-(4-(6-(Difluoro-(tetrahydro-2H-pyran-4-yl)methyl)pyridin-2- 2I, 11yl)benzyl)-3-(2-oxo-propyl)imidazolidine-2,4-dione ¹H NMR (400 MHz,CDCl₃): δ 8.05 (d, J = 8.22, 2H), 7.87 (dd, J = 8.22 and 7.43 Hz, 1H),7.80 (d, J = 7.43 Hz, 1H), 7.56 (d, J = 8.22 Hz, 1H), 7.39 (d, J = 8.33Hz, 2H), 4.62 (s, 2H), 4.37 (s, 2H), 4.05- 4.00 (m, 2H), 3.87 (s, 2H),3.42 (td, J = 11.74 and 2.35 Hz, 2H), 2.91-2.78 (m, 1H), 2.26 (s, 3H),1.76-1.62 (m, 4H). 55 3-(2-Oxo-propyl)-1-(4-(6-((tetrahydro-2H-pyran-3-2I, 6J ylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR(400 MHz, CDCl₃): δ 8.01 (d, J = 8.22, 2H), 7.72 (dd, J = 8.22 and 7.43Hz, 1H), 7.59 (d, J = 7.83 Hz, 1H), 7.37 (d, J = 8.22 Hz, 2H), 7.25 (d,J = 7.43 Hz, 1H), 4.65 (s, 2H), 4.37 (s, 2H), 4.02- 3.96 (m, 3H), 3.86(s, 2H), 3.85-3.77 (m, 1H), 3.50-3.39 (m, 2H), 3.30-3.22 (m, 1H),2.79-2.70 (m, 1H), 2.25 (s, 3H), 2.07- 1.98 (m, 1H), 1.76-1.62 (m, 3H).56 1-(4-(6-((3-Oxo-piperidin-1-yl)methyl)pyridin-2-yl)benzyl)-3-(2-oxo-2I, 6G propyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 8.00(d, J = 8.22, 2H), 7.74 (dd, J = 7.83 and 7.43 Hz, 1H), 7.60 (d, J =7.83 Hz, 1H), 7.41-7.35 (m, 3H), 4.65 (s, 2H), 4.37 (s, 2H), 3.85 (bs,4H), 3.15 (s, 2H), 3.82- 2.76 (m, 2H), 2.44-2.37 (m, 2H), 2.25 (s, 3H),2.05-1.96 (m, 2H). 573-Isopropyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2- 3, 5yl)benzyl)imidazolidine-2,4-dione 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J= 8.61 Hz, 2H), 7.72 (dd, J = 7.83 and 7.43 Hz, 1H), 7.56 (d, J = 7.83Hz, 1H), 7.43 (d, J = 7.43 Hz, 1H), 7.34 (d, J = 8.61 Hz, 2H), 4.58 (s,2H), 4.40-4.32 (m, 1H), 3.72 (s, 2H), 3.67 (s, 2H), 2.50 (bs, 4H),1.66-1.57 (m, 6H), 1.44 (d, J = 7.04 Hz, 6H). 581-(4-(5-Fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3- 3, 7Disopropylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, J =8.22 Hz, 2H), 7.62 (dd, J = 7.83 and 3.52 Hz, 1H), 7.42 (dd, J = 9.00and 8.61 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H), 4.58 (m, 2H), 4.40-4.31 (m,1H), 3.83 (s, 2H), 3.67 (s, 2H), 2.62-2.55 (m, 4H), 1.64-1.56 (m, 4H),1.46- 1.38 (m, 8H). 591-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2- 3,7^(a) yl)benzyl)-3-isopropylimidazolidine-2,4-dione ¹H NMR (400 MHz,DMSO): δ 8.05 (d, J = 8.22, 2H), 7.99 (dd, J = 8.61 and 3.52 Hz, 1H),7.81 (dd, J = 9.39 and 8.61 Hz, 1H), 7.39 (d, J = 8.22 Hz, 2H), 4.53 (s,2H), 4.24-4.15 (m, 1H), 3.95 (bs, 2H), 3.86 (s, 2H), 3.15-3.02 (m, 8H),1.34 (d, J = 6.65 Hz, 6H). 601-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)pyridin-2- 3, 6Ayl)benzyl)-3-isopropylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.98 (d, J = 8.22, 2H), 7.77 (dd, J = 7.83 and 7.43 Hz, 1H), 7.63 (d, J= 7.83 Hz, 1H), 7.39-7.32 (m, 3H), 4.60 (s, 2H), 4.41-4.30 (m, 1H), 3.92(s, 2H), 3.68 (s, 2H), 3.19-3.08 (m, 8H), 1.44 (d, J = 7.04 Hz, 6H). 613-Cyclopropyl-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2- 4A, 7Dyl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, J= 8.22 Hz, 2H), 7.62 (dd, J = 8.61 and 3.52 Hz, 1H), 7.42 (dd, J = 8.61and 8.22 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H), 4.58 (s, 2H), 3.82 (d, J =2.74 Hz, 2H), 3.68 (s, 2H), 2.67-2.55 (m, 5H), 1.64-1.54 (m, 4H),1.44-1.84 (m, 2H), 1.83-1.75 (m, 2H), 1.64-1.57 (m, 4H), 1.47-1.37 (m,2H), 1.00-0.95 (m, 4H). 623-Cyclopropyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2- 4A, 5yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, J= 8.22 Hz, 2H), 7.72 (dd, J = 7.83 and 7.43 Hz, 1H), 7.56 (d, J = 7.83Hz, 1H), 7.43 (d, J = 7.43 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H), 4.59 (s,2H), 3.72 (s, 2H), 3.67 (s, 2H), 2.66-2.60 (m, 1H), 2.54-2.46 (m, 4H),1.65-1.57 (m, 2H), 1.50-1.42 (m, 2H), 1.00-0.96 (m, 4H). 633-Cyclopropyl-1-(4-(5-fluoro-6-((tetrahydro-2H-pyran-4- 4A, 7Iylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400MHz, CDCl₃): δ 7.95 (d, J = 8.22 Hz, 2H), 7.62 (dd, J = 8.61 and 3.51Hz, 1H), 7.43 (dd, J = 9.00 and 8.61 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H),4.59 (s, 2H), 4.09 (d, J = 1.96 Hz, 2H), 4.04-3.97 (m, 2H), 3.70 (s,2H), 3.42 (Td, J = 11.74 and 2.35 Hz, 2H), 2.84-2.74 (m, 1H), 2.67-2.60(m, 1H), 1.95-1.87 (m, 2H), 1.61-1.49 (m, 2H), 0.99-0.96 (m, 4H). 643-Cyclopropyl-1-(4-(6-((tetrahydro-2H-pyran-4- 4A, 6Hylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400MHz, CDCl₃): δ 7.99 (d, J = 8.61 Hz, 2H), 7.72 (dd, J = 7.83 and 7.43Hz, 1H), 7.59 (d, J = 7.83 Hz, 1H), 7.36 (d, J = 8.61 Hz, 2H), 7.26 (d,J = 7.43, 1H), 4.59 (s, 2H), 4.04-3.97 (m, 4H), 3.69 (s, 2H), 3.42 (Td,J = 11.74 and 1.96 Hz, 2H), 2.84- 2.74 (m, 1H), 2.67-2.59 (m, 1H),1.95-1.87 (m, 2H), 1.55-1.44 (m, 2H), 0.98-0.95 (m, 4H). 653-Cyclopropyl-1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4- 4A, 6^(a)ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz,CDCl₃): δ 7.98 (d, J = 8.22 Hz, 2H), 7.77 (dd, J = 7.83 and 7.43 Hz,1H), 7.63 (d, J = 7.83 Hz, 1H), 7.36 (m, 3H), 4.59 (s, 2H), 3.92 (s,2H), 3.69 (s, 2H), 3.18-3.08 (m, 8H), 2.67- 2.59 (m, 1H), 0.98 (m, 4H).66 3-Cyclopropyl-1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5- 4A,7^(a) fluoro-pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400MHz, CDCl₃): δ 7.93 (d, J = 8.22 Hz, 2H), 7.68 (dd, J = 7.83 and 7.43Hz, 1H), 7.63 (dd, J = 9.00 and 3.52 Hz, 1H), 7.36 (d, J = 8.22 Hz, 2H),4.59 (s, 2H), 4.02 (s, 2H), 3.70 (s, 2H), 3.24-3.19 (m, 4H), 3.13-3.07(m, 4H), 2.67-2.59 (m, 1H), 1.01- 0.96 (m, 4H). 673-Cyclobutyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2- 4B, 5yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, J= 8.22 Hz, 2H), 7.72 (dd, J = 7.83 and 7.43 Hz, 1H), 7.56 (d, J = 7.83Hz, 1H), 7.43 (d, J = 7.43 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H), 4.63-4.53(m, 3H), 3.72 (s, 2H), 3.67 (s, 2H), 2.97-2.84 (m, 2H), 2.54-2.46 (m,4H), 2.24- 2.14 (m, 2H), 1.92-1.82 (m, 1H), 1.79-1.67 (m, 1H), 1.65-1.57 (m, 4H), 1.52-1.40 (m, 2H). 683-Cyclobutyl-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2- 4B, 7Dyl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.96 (d, J= 8.22 Hz, 2H), 7.61 (dd, J = 8.61 and 3.52 Hz, 1H), 7.42 (dd, J = 9.00and 8.61 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H), 4.59 (s, 2H), 3.83 (s, 2H),3.68 (s, 2H), 2.96-2.85 (m, 2H), 2.63-2.54 (m, 4H), 2.24-2.13 (m, 2H),1.92- 1.82 (m, 1H), 1.78-1.67 (m, 1H), 1.64-1.56 (m, 4H), 1.45-1.37 (m,2H). 69 3-Cyclobutyl-1-(4-(5-fluoro-6-((tetrahydro-2H-pyran-4- 4B, 7Iylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400MHz, CDCl₃): δ 7.95 (d, J = 8.22 Hz, 2H), 7.61 (dd, J = 8.61 and 3.52Hz, 1H), 7.42 (dd, J = 9.00 and 8.61 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H),4.64-4.53 (m, 3H), 4.08 (bs, 2H), 4.04- 3.97 (m, 2H), 3.69 (s, 2H), 3.42(td, 11.74 and 1.96 Hz, 2H), 2.96- 2.83 (m, 2H), 2.83-2.73 (m, 1H),2.25-2.13 (m, 2H), 1.96-1.82 (m, 3H), 1.78-1.67 (m, 1H), 1.61-1.59 (m,2H). 70 3-Cyclobutyl-1-(4-(6-((tetrahydro-2H-pyran-4- 4B, 6Hylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400MHz, CDCl₃): δ 8.00 (d, J = 8.22 Hz, 2H), 7.72 (dd, J = 7.83 and 7.43Hz, 1H), 7.42 (d, J = 7.83 Hz, 1H), 7.36 (d, J = 8.22 Hz, 2H), 7.25 (d,J = 7.43 Hz, 1H), 4.63-4.53 (m, 3H), 4.05- 3.96 (m, 4H), 3.69 (s, 2H),3.42 (td, 11.74 and 2.35 Hz, 2H), 2.96- 2.84 (m, 2H), 2.83-2.74 (m, 1H),2.24-2.14 (m, 2H), 1.95-1.82 (m, 3H), 1.77-1.67 (m, 1H), 1.58-1.46 (m,2H). 71 3-Cyclobutyl-1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-4B, 7^(a) fluoro-pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400MHz, DMSO): δ 8.05 (d, J = 8.22, 2H), 7.99 (dd, J = 8.61 and 3.52 Hz,1H), 7.81 (dd, J = 9.39 and 8.61 Hz, 1H), 7.40 (d, J = 8.22 Hz, 2H),4.53 (s, 2H), 4.51-4.40 (m, 1H), 3.96 (bs, 2H), 3.86 (s, 2H), 3.15-3.01(m, 8H), 2.83-2.71 (m, 2H), 2.15- 2.04 (m, 2H), 1.77-1.65 (m, 2H). 723-Cyclobutyl-1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4- 4B, 6^(a)ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz,CDCl₃): δ 7.98 (d, J = 8.22, 2H), 7.77 (dd, J = 7.83 and 7.43 Hz, 1H),7.63 (d, J = 7.83 Hz, 1H), 7.39-7.32 (m, 3H), 4.64-4.52 (m, 3H), 3.93(s, 2H), 3.86 (s, 2H), 3.19-3.08 (m, 8H), 2.96-2.85 (m, 2H), 2.25-2.14(m, 2H), 1.93-1.82 (m, 1H), 1.78-1.66 (m, 1H). 731-(4-(6-(Piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(2,2,2- 4C, 5trifluoroethyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 8.00(d, J = 8.22 Hz, 2H), 7.73 (dd, J = 7.83 and 7.43 Hz, 1H), 7.56 (d, J =7.83 Hz, 1H), 7.44 (d, J = 7.43 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.64(s, 2H), 4.17 (q, J = 8.61 Hz, 2H), 3.84 (s, 2H), 3.72 (s, 2H),2.54-2.46 (m, 4H), 1.67- 1.56 (m, 4H), 1.51-1.42 (m, 2H). 741-(4-(6-((3,3-Dimethylpiperidin-1-yl)methyl)-5-fluoropyridin-2- 4C, 7Eyl)benzyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione ¹H NMR (400MHz, CDCl₃): δ 7.96 (d, J = 8.61 Hz, 2H), 7.61 (dd, J = 8.61 and 3.52Hz, 1H), 7.41 (dd, J = 9.00 and 8.61 Hz, 1H), 7.35 (d, J = 8.61 Hz, 2H),4.61 (s, 2H), 3.79 (d, J = 2.35 Hz, 2H), 4.08 (d, J = 2.75 Hz, 2H),4.04-3.98 (m, 2H), 3.87 (s, 2H), 3.74 (s, 2H), 3.61 (q, J = 7.04 Hz,2H), 2.49 (bs, 2H), 2.19 (bs, 2H), 1.64-1.55 (m, 2H), 1.27-1.22 (t, J =7.04 Hz, 3H), 1.21-1.16 (m, 2H), 0.93 (s, 6H). 751-(4-(5-Fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(2,2,2-4C, 7D trifluoro-ethyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃):δ 7.98 (d, J = 8.22, 2H), 7.63 (dd, J = 8.21 and 3.52 Hz, 1H), 7.43 (dd,J = 9.00 and 8.61 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.64 (s, 2H), 4.19(d, J = 8.61 Hz, 1H), 4.15 (d, J = 8.61 Hz, 1H), 3.87-3.82 (m, 4H),2.64-2.54 (m, 4H), 1.65- 1.56 (m, 4H), 1.46-1.37 (m, 2H). 761-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)pyridin-2- 4C, 6^(a)yl)benzyl)-3-(2,2,2-trifluoro-ethyl)imidazolidine-2,4-dione ¹H NMR (400MHz, CDCl₃): δ 8.00 (d, J = 8.22, 2H), 7.77 (dd, J = 7.83 and 7.43 Hz,1H), 7.64 (d, J = 7.83 Hz, 1H), 7.41-7.34 (m, 3H), 4.65 (s, 2H), 4.20(d, J = 8.22 Hz, 1H), 4.15 (d, J = 8.22 Hz, 1H), 3.93 (s, 2H), 3.85 (m,2H), 3.20-3.08 (m, 8H). 771-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoro-pyridin- 4C,7^(a) 2-yl)benzyl-3-(2,2,2-trifluoro-ethyl)imidazolidine-2,4-dione ¹HNMR (400 MHz, CDCl₃): δ 7.96 (d, J = 8.22, 2H), 7.69 (dd, J = 7.83 and7.43 Hz, 1H), 7.49 (d, J = 7.83 Hz, 1H), 7.37 (d, J = 8.22 Hz, 2H), 4.65(s, 2H), 4.20 (d, J = 8.22 Hz, 1H), 4.15 (d, J = 8.22 Hz, 1H), 4.02 (d,J = 2.35 Hz, 2H), 3.86 (s, 2H), 3.25-3.18 (m, 4H), 3.13-3.06 (m, 4H). 781-(4-(6-((Tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2- 4C, 6Hyl)benzyl)-3-(2,2,2-trifluoro-ethyl)imidazolidine-2,4-dione ¹H NMR (400MHz, CDCl₃): δ 8.02 (d, J = 8.22, 2H), 7.73 (dd, J = 7.83 and 7.43 Hz,1H), 7.60 (d, J = 7.83 Hz, 1H), 7.37 (d, J = 8.22 Hz, 2H), 7.22 (d, J =7.43 Hz, 1H), 4.65 (s, 2H), 4.20 (d, J = 8.22 Hz, 1H), 4.15 (d, J = 8.22Hz, 1H), 4.03-3.96 (m, 4H), 3.85 (s, 2H), 3.41 (td, J = 11.74 and 2.35Hz, 2H), 2.85-2.75 (m, 1H), 1.96-1.86 (m, 2H), 1.54-1.47 (m, 2H). 791-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin- 4C, 7I2-yl)benzyl)-3-(2,2,2-trifluoro-ethyl)imidazolidine-2,4-dione ¹H NMR(400 MHz, CDCl₃): δ 7.97 (d, J = 8.22, 2H), 7.62 (dd, J = 7.83 and 7.43Hz, 1H), 7.44 (dd, J = 9.00 and 8.61 Hz, 1H), 7.37 (d, J = 8.22 Hz, 2H),4.65 (s, 2H), 4.20 (d, J = 8.61 Hz, 1H), 4.16 (d, J = 8.61 Hz, 1H), 4.08(bs, 2H), 4.04-3.98 (m, 2H), 3.86 (s, 2H), 3.46 (td, J = 11.74 and 2.35Hz, 2H), 2.83-2.73 (m, 1H), 1.95-1.88 (m, 2H), 1.60-1.49 (m, 2H). 803-((R)-1-Cyclopropylethyl)-1-(4-(5-fluoro-6-(piperidin-1- 4D, 7Dylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz,CDCl₃): δ 7.97 (d, J = 8.22 Hz, 2H), 7.63 (dd, J = 8.61 and 3.91 Hz,1H), 7.43 (d, J = 9.00 and 8.61 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.60(s, 2H), 3.83 (bs, 2H), 3.71 (s, 2H), 2.63-2.54 (m, 4H), 2.32-2.25 (m,1H), 1.65-1.50 (m, 4H), 1.46- 1.35 (m, 2H), 0.66-0.58 (m, 1H), 0.50-0.41(m, 1H), 0.29- 0.24 (m, 2H). 81(S)-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(1-4E, 7D methoxypropan-2-yl)imidazolidine-2,4-dione ¹H NMR (400 MHz,CDCl₃): δ 7.96 (d, J = 8.22 Hz, 2H), 7.62 (dd, J = 8.61 and 3.52 Hz,1H), 7.42 (d, J = 9.00 and 8.61 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H), 4.62(d, J = 14.87 Hz, 1H), 4.56 (d, J = 15.26 Hz, 1H), 4.49-4.39 (m, 1H)3.95 (t, J = 9.78 Hz, 1H), 3.83 (d, J = 2.74 Hz, 2H), 3.71 (s, 2H), 3.45(dd, J = 9.78 and 5.48 Hz, 1H), 3.35 (s, 3H), 2.62-2.35 (m, 4H),1.63-1.54 (m, 4H), 1.46- 1.34 (m, 5H). 821-(4-(6-(Piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3- 4F, 5(tetrahydrofuran-3-yl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.99 (d, J = 8.22 Hz, 2H), 7.72 (dd, J = 7.83 and 7.43 Hz, 1H), 7.56 (d,J = 7.83 Hz, 1H), 7.43 (d, J = 7.43 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H),4.80-4.71 (m, 1H), 4.59 (s, 32H), 4.20-4.11 (m, 1H), 4.05-3.85 (m, 3H),3.72 (bs, 4H), 2.53-2.45 (m, 4H), 2.42-2.32 (m, 1H), 2.26-2.15 (m, 1H),1.65- 1.56 (m, 4H), 1.52-1.40 (m, 2H). 831-(4-(5-Fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3- 4F, 7D(tetrahydrofuran-3-yl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ7.96 (d, J = 8.22 Hz, 2H), 7.62 (dd, J = 8.61 and 3.52 Hz, 1H), 7.43(dd, J = 9.00 and 8.61 Hz, 1H), 7.34 (d, J = 8.22 Hz, 2H), 4.81-4.70 (m,1H), 4.60 (s, 2H), 4.20- 4.12 (m, 1H), 4.05-3.85 (m, 3H), 3.83 (d, J =2.74 Hz, 2H), 3.73 (s, 2H), 2.63-2.54 (m, 4H), 2.42-2.33 (m, 1H),2.26-2.15 (m, 1H), 1.64-1.54 (m, 4H), 1.46-1.38 (m, 2H). 841-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin- 4F, 7I2-yl)benzyl)-3-(tetrahydro-furan-3-yl)imidazolidine-2,4-dione ¹H NMR(400 MHz, CDCl₃): δ 7.96 (d, J = 8.22 Hz, 2H), 7.62 (dd, J = 8.61 and3.52 Hz, 1H), 7.43 (dd, J = 9.00 and 8.61 Hz, 1H), 7.36 (d, J = 8.22 Hz,2H), 4.80-4.70 (m, 1H), 4.60 (s, 2H), 4.19- 4.12 (m, 1H), 4.08 (d, J =1.96 Hz, 2H), 4.04-3.86 (m, 5H), 3.74 (s, 2H), 3.42 (td, J = 11.74 and1.96 Hz, 2H), 2.84-2.73 (m, 1H), 2.43-2.32 (m, 1H), 2.25-2.15 (m, 1H),1.95-1.87 (m, 2H), 1.61- 1.47 (m, 2H). 853-Cyclobutyl-1-(4-(5-fluoro-6-(thiomorpholinomethyl)pyridin-2- 4B, 7Lyl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, J= 8.22 Hz, 2H), 7.64 (dd, J = 8.61 and 3.52 Hz, 1H), 7.44 (dd, J = 9.00and 8.61 Hz, 1H), 7.35 (d, J = 8.61 Hz, 2H), 4.59-4.53 (m, 3H), 3.88 (d,J = 2.35 Hz, 2H), 3.68 (s, 2H), 2.96-2.85 (m, 6H), 2.72-2.68 (m, 4H),2.24-2.14 (m, 2H), 1.92-1.81 (m, 1H), 1.78-1.67 (m, 1H). 863-Cyclobutyl-1-(4-(6-(thiomorpholinomethyl)pyridin-2- 4B, 6Kyl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, J= 8.22 Hz, 2H), 7.73 (dd, J = 7.83 and 7.43 Hz, 1H), 7.58 (d, J = 7.83Hz, 1H), 7.40 (d, J = 7.43 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.61-4.55(m, 3H), 3.78 (s, 2H), 3.67 (s, 2H), 2.94-2.82 (m, 6H), 2.75-2.69 (m,4H), 2.24- 2.14 (m, 2H), 1.92-1.80 (m, 1H), 1.80-1.68 (m, 1H). 871-(4-(5-Fluoro-6-(thiomorpholinomethyl)-pyridin-2-yl)benzyl)-3- 2C, 7Lpropylimidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, J =8.61 Hz, 2H), 7.64 (dd, J = 8.61 and 3.52 Hz, 1H), 7.44 (dd, J = 9.00and 8.61 Hz, 1H), 7.35 (d, J = 8.61 Hz, 2H), 4.62 (s, 2H), 3.89 (d, J =2.35 Hz, 2H), 3.75 (s, 2H), 3.54-3.49 (m, 2H), 2.95-2.89 (m, 4H),2.73-2.68 (m, 4H), 1.74-1.61 (m, 2H), 0.95 (t, J = 7.43 Hz, 3H). 883-Propyl-1-(4-(6-(thiomorpholinomethyl)pyridin-2- 2C, 6Kyl)benzyl)imidazolidine-2,4-dione ¹H NMR (400 MHz, CDCl₃): δ 7.98 (d, J= 8.22 Hz, 2H), 7.73 (dd, J = 7.83 and 7.43 Hz, 1H), 7.58 (d, J = 7.83Hz, 1H), 7.40 (d, J = 7.43 Hz, 1H), 7.35 (d, J = 8.22 Hz, 2H), 4.62 (s,2H), 3.78 (d, J = 2.35 Hz, 2H), 3.73 (s, 2H), 3.54-3.48 (m, 2H),2.86-2.82 (m, 4H), 2.75-2.68 (m, 4H), 1.74-1.62 (m, 2H), 0.94 (t, J =7.43 Hz, 3H).

EXAMPLE 891-(4-(6-(Piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione

i) To a solution of 2-bromo-6-piperidin-1-ylmethyl-pyridine (example 5)(8.0 g, 31.4 mmol) and 4-formylphenylboronic acid (6.1 g, 40.8 mmol) intoluene/ethanol (4/1, 320 ml) was added an aqueous solution of 2Mpotassium carbonate. After 15 minutes stirring under a nitrogenatmosphere, tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.02 mmol)was added. After stirring for 17 h at 80° C. under a nitrogenatmosphere, the mixture was cooled to room temperature and filteredthrough decalite. Water was added and the product was extracted intoethylacetate. The combined organic phases were washed with water, brine,dried over sodium sulfate and concentrated under reduced pressure.Column chromatography afforded4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzaldehyde (7.69 g) as a whitesolid.

ii) A solution of glycine methylester.HCl (4.79 g, 38.1 mmol) andtriethylamine 4.60 ml, 33.0 mmol) in methanol (70 ml) was added dropwiseto a solution of the product obtained in the previous step (7.12 g, 25.4mmol) in methanol (70 ml) under a nitrogen atmosphere. After stirringfor 1 h at room temperature, sodium sodium triacetoxyborohydride (12.9g, 61.0 mmol) was added portion wise during a 30 minutes period of time.After 17 h stirring more glycine methylester.HCl (1.6 g, 12.7 mmol) wasadded, followed by addition of sodium triacetoxyborohydride (5.38 g,25.4 mmol). After stirring for another 17 h the reaction mixture wasquenched by the addition of a saturated aqueous solution of sodiumhydrogen carbonate. The product was extracted into dichloromethane andthe combined organic phases were washed with water, brine, filteredthrough a phase separation filtered and concentrated under reducedpressure. Column chromatography afforded methyl2-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzylamino)acetate (3.48 g)as a white solid.

iii) To a suspension of the product obtained in the previous step (8.03g, 22.7 mmol) in dioxane/water (1/1) (100 ml) was added at roomtemperature, potassium cyanate (2.76 g, 34.1 mmol). After 20 minutesstirring, acetic acid (4.16 ml, 72.7 mmol) was added and the mixture wasstirred for another 17 h at room temperature. The reaction mixture wasquenched by the addition of water and basified by the addition of asaturated aqueous solution of sodium hydrogen carbonate until pH=9. Theproduct was extracted into dichloromethane and the combined organicphases were washed with brine, filtered through a phase separationfilter and concentrated under reduced pressure to afford methyl2-(1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)ureido)acetate (8.2g) as an oil. The product was used in the following step without furtherpurification.

iv) To a solution of the product obtained in the previous step (8.2 g,20.68 mmol) in methanol (50 ml) was added at room temperature, sodiummethoxide (2.24 g, 41.4 mmol) and the reaction mixture was stirred for 3h at room temperature under a nitrogen atmosphere. The reaction mixturewas poured into water and neutralized by the addition of a saturatedaqueous solution of ammonium chloride. The product was extracted intodichloromethane and the combined organic phases were washed with brine,dried over sodium sulfate and concentrated under reduced pressure.Column chromatography afforded the title compound1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione(5.8 g) as a white solid.

1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.61 Hz, 2H), 7.72 (dd, J=7.83 and7.43 Hz, 1H), 7.57 (d, J=7.83 Hz, 1H), 7.42 (d, J=7.43 Hz, 1H), 7.34 (d,J=8.61 Hz, 2H), 4.57 (s, 2H), 3.77 (s, 2H), 3.73 (s, 2H), 2.56-2.48 (m,4H), 1.67-1.57 (m, 4H), 1.50-1.42 (m, 2H).

EXAMPLE 901-(4-(6-(Piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(3,3,3-trifluoro-propyl)imidazolidine-2,4-dione

i) A solution of1-(4-(6-Piperidin-1-ylmethyl-pyridin-2-yl)benzyl)imidazolidine-2,4-dione(example 134) (120 mg, 0.33 mmol), potassium carbonate (137 mg, 0.99mmol) and 3-bromo-1,1,1-trifluoropropane (117 mg, 0.66 mmol) in DMF (2.5ml) was stirred during 17 h at 50° C. After cooling to room temperaturethe reaction mixture was quenched by the addition of water. The productwas extracted into ethylacetate and the combined organic phases werewashed with brine, dried over sodium sulfate and concentrated underreduced pressure. Column chromatography afforded the title compound (50mg) as a white solid.

1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.61 Hz, 2H), 7.72 (dd, J=7.83 and7.43 Hz, 1H), 7.56 (d, J=7.83 Hz, 1H), 7.44 (d, J=7.43 Hz, 1H), 7.33 (d,J=8.61 Hz, 2H), 4.62 (s, 2H), 3.83 (t, J=7.04 Hz, 2H), 3.76 (s, 2H),3.73 (s, 2H), 2.60-2.45 (m, 6H), 1.66-1.59 (m, 4H), 1.51-1.41 (m, 2H).

EXAMPLE 91

Following a procedure analogous to that described in Example 90 thefollowing compounds were prepared.

91A:4-(2,5-Dioxo-3-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidin-1-yl)butanenitrile

1H NMR (400 MHz, CDCl3): δ 8.00 (d, J=8.61 Hz, 2H), 7.72 (dd, J=7.83 and7.43 Hz, 1H), 7.56 (d, J=7.83 Hz, 1H), 7.43 (d, J=7.43 Hz, 1H), 7.35 (d,J=8.61 Hz, 2H), 4.62 (s, 2H), 3.78 (s, 2H), 3.72 (s, 2H), 3.69 (t,J=6.65 Hz, 2H), 2.54-2.47 (m, 4H), 2.44 (t, J=7.04 Hz, 2H), 2.05 (m,2H), 1.65-1.56 (m, 4H), 1.50-1.40 (m, 2H).

91B: (R)-methyl3-(2,5-dioxo-3-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidin-1-yl)-2-methylpropanoate

1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.22 Hz, 2H), 7.72 (dd, J=7.83 and7.43 Hz, 1H), 7.56 (d, J=7.83 Hz, 1H), 7.43 (d, J=7.43 Hz, 1H), 7.34 (d,J=8.22 Hz, 2H), 4.61 (s, 2H), 3.83 (dd, J=13.69 and 7.83 Hz, 1H), 3.75(s, 2H), 3.72 (s, 2H), 3.69 (s, 3H), 3.63 (dd, J=14.09 and 6.65 Hz, 1H),3.00-2.90 (m, 1H), 2.54-2.46 (m, 4H), 1.65-1.54 (m, 4H), 1.51-1.41 (m,2H), 1.20 (d, J=7.04 Hz, 3H).

91C:3-(Oxetan-2-ylmethyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.61 Hz, 2H), 7.72 (dd, J=7.83 and7.43 Hz, 1H), 7.56 (d, J=7.83 Hz, 1H), 7.43 (d, J=7.43 Hz, 1H), 7.34 (d,J=8.61 Hz, 2H), 5.08-5.00 (m, 1H), 4.70-4.56 (m, 4H), 3.99-3.93 (dd,J=14.08 and 7.43 Hz, 1H), 3.78-3.70 (m, 5H), 2.78-2.70 (m, 1H),2.55-2.45 (m, 4H), 1.66-1.58 (m, 5H), 1.50-1.41 (m, 2H).

91D:3-(2-Oxotetrahydrofuran-3-yl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 8.00 (d, J=8.61 Hz, 2H), 7.73 (dd, J=7.83 and7.43 Hz, 1H), 7.57 (d, J=7.83 Hz, 1H), 7.44 (d, J=7.43 Hz, 1H), 7.36 (d,J=8.61 Hz, 2H), 4.97-4.90 (m, 1H), 4.65-4.56 (m, 5H), 4.39-4.31 (m, 1H),3.82 (s, 2H), 3.73 (s, 2H), 2.84-2.72 (m, 1H), 2.59-2.47 (m, 5H),1.66-1.57 (m, 4H), 1.50-1.42 (m, 2H).

91E:1-(4-(6-(Piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(tetrahydrofuran-2-yl)imidazolidine-2,4-dione

1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.22 Hz, 2H), 7.72 (dd, J=7.83 and7.43 Hz, 1H), 7.56 (d, J=7.83 Hz, 1H), 7.43 (d, J=7.43 Hz, 1H), 7.34 (d,J=8.22 Hz, 2H), 4.65 (d, J=15.26 Hz, 1H), 4.58 (d, J=15.26 Hz, 1H),4.30-4.22 (m, 1H), 3.96-3.88 (m, 1H), 3.81-3.64 (m, 6H), 3.50 (dd,J=13.69 and 4.70 Hz, 1H), 2.55-2.45 (m, 4H), 2.08-1.84 (m, 3H),1.72-1.57 (m, 5H), 1.50-1.42 (m, 2H).

EXAMPLE 92 2-Amino-N-cyclopropylacetamide trifluoroacetate

i) TBTU (5.1 g, 16.5 mmol), DIPEA (2.9 ml, 16.5 mmol) andcyclopropylamine (2.2 ml, 33 mmol) were added to a solution ofBOC-Gly-OH (2.63 g, 15 mmol) in dry dichloromethane (10 ml). After 17 hstirring, the reaction mixture was concentrated under reduced pressureand water was added to the residue. The product was extracted into ethylacetate. The combined organic phases were washed with an aqueoussolution of 2M hydrochloric acid, a saturated aqueous solution of sodiumhydrogen carbonate, brine, dried over sodium sulfate and concentratedunder reduced pressure to give 2-tert-butyl2-(cyclopropylamino)-2-oxoethylcarbamate (847 mg). The product was usedin the following step without further purification.

ii) TFA (65 ml, 875 mmol) was added to a solution of the productobtained in the previous step (34.9 g, 163 mmol) in dichloromethane (300ml). After 17 h stirring the reaction mixture was concentrated underreduced pressure. Crystallization from DCM/diisopropyletheretherafforded the title compound 2-Amino-N-cyclopropylacetamidetrifluoroacetate

(22.2 g). 1H NMR (400 MHz, MeOD): δ 3.62 (s, 2H), 2.76-2.74 (m, 1H),0.75 (m, 2H), 0.52 (m, 2H)

EXAMPLE 933-Cyclopropyl-1-(3-fluoro-4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione

i)3-Fluoro-4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzaldehydewas prepared following a procedure analogous to that described inExample 89, step i), using 2-fluoro-4-formylphenylboronic acid as thestarting material.

ii) To a solution of the product obtained in the previous step (1.3 g,4.1 mmol) in methanol (60 ml) were added at 0° C. KOH (4.6 mg, 0.08mmol) and 2-amino-N-cyclopropyl-acetamide trifluoroacetate (1.9 g, 8.22mmol). After 30 minutes at 0° C. sodium triacetoxy borohydride (2.6 g,12.3 mmol) was added. After 17 h stirring at room temperature thereaction mixture was quenched by addition of a saturated aqueoussolution of sodium hydrogen carbonate and the product was extracted intodichloromethane. The combined organic phases were washed with water,brine, dried over sodium sulphate and concentrated under reducedpressure. Column chromatography affordedN-cyclopropyl-2-(3-fluoro-4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzylamino)acetamide(0.6 g).

iii) Following a procedure analogous to that described in Example 3,step iii), the product obtained in the previous step (0.28 g), wasconverted to the title compound3-Cyclopropyl-1-(3-fluoro-4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione(43 mg).

¹H NMR (400 MHz, CDCl₃): δ 8.00 (dd, J=8.22 and 7.83 Hz, 1H), 7.74-7.68(m, 1H), 7.43 (dd, J=9.00 and 8.61 Hz, 1H), 7.15 (dd, J=8.22 and 1.96Hz, 1H), 7.06 (dd, J=11.74 and 1.57 Hz, 1H), 4.57 (s, 2H), 3.81 (d,J=2.35 Hz, 2H), 3.71 (s, 2H), 2.68-2.53 (m, 5H), 1.65-1.50 (m, 4H),1.46-1.38 (m, 2H), 1.00 (s, 2H), 0.98 (s, 2H).

EXAMPLE 941-(3-Fluoro-4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione

i) 3-Fluoro-4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzaldehyde wasprepared following a procedure analogous to that described in Example89, step i), using 2-Fluoro-4-formylphenylboronic acid as the startingmaterial.

ii) Following a procedure analogous to that described in Example 93,step ii), the product obtained in the previous step (1 g), was convertedusing glycinamide hydrochloric acid as the starting material to2-(3-Fluoro-4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzylamino)-acetamide(0.9 g).

iii) Following a procedure analogous to that described in Example 3,step iii), the product obtained in the previous step (0.9 g), wasconverted to1-(3-Fluoro-4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione(0.49 g).

iv) Following a procedure analogous to that described in Example 90,step i, the product obtained in the previous step (0.49 g), wasconverted to1-(3-Fluoro-4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione(52 mg).

¹H NMR (400 MHz, CDCl₃): δ 8.00 (dd, J=8.22 and 7.83 Hz, 1H), 7.73 (dd,J=7.83 and 7.43 Hz, 1H), 7.65-7.60 (m, 1H), 7.46 (d, J=7.83 Hz, 1H),7.14 (dd, J=7.83 and 1.57 Hz, 1H), 7.05 (dd, J=11.74 and 1.57 Hz, 1H),4.60 (s, 2H), 3.77 (s, 2H), 3.71 (s, 2H), 3.37 (d, J=7.43 Hz, 2H),2.53-2.45 (m, 4H), 2.14-2.06 (m, 1H), 1.65-1.57 (m, 4H), 1.50-1.42 (m,2H), 0.94 (d, J=6.65 Hz, 6H).

EXAMPLE 95 Agonist Induced cAMP Change in Human CB2 Transfected CHOCells

Adenylate cyclase assays were carried out using CHO cells stablyover-expressing the human recombinant CB2 receptor. Cells were culturedin DMEM/HAMF12 containing 1% (v/v) penicillin/streptomycin (Gibco15140-122), 10% Fetal Bovine Serum (FBS) and 400 μg/ml Geneticin(Invitrogen 10131-027). Compounds and reference (CP55,940) weredissolved in DMSO and dilutions were made in serum free mediumcontaining 2 μM Rolipram (Sigma R6520) and 1 μM Forskolin (Sigma,F3917). 10 μl of each dilution was transferred to an assay plate(384-well white culture plate, Perkin Elmer). Cell suspensionscontaining 5×10⁵ cells/ml in DMEM/HAMF12 containing 1% (v/v)penicillin/streptomycin were prepared from hCB2_C2-CHO cells and 10 μl(5,000 cells/well) thereof was transferred to the assay plate and cellswere incubated for 45 min at 37° C. Homogeneous time-resolvedfluorescence (HTRF; CisBio) was used as a read-out by sequentiallyadding 10 μl cAMP-XL665 and 10 μl anti-cAMP(Eu) cryptate; after 1 hincubation at room temperature, fluorescence at 615 nm and 665 nm wasmeasured on Envision (Perkin Elmer). Results were calculated from the665 nm/615 nm ratios obtained for individual compounds and were comparedto values obtained for the reference compound. The compounds fromExamples 12-88, 90, 91, 93 and 94 have an EC₅₀≦1×10⁻⁷ M for CB2.

EXAMPLE 95A Agonist-Induced cAMP Change in Human CB1 Transfected CHOCells

Adenylate cyclase assays were carried out using CHO cells stablyover-expressing the human recombinant CB1 receptor. Cells were culturedin DMEM/HAMF12 containing 1% (v/v) penicillin/streptomycin (Gibco15140-122), 10% Fetal Bovine Serum (FBS), 400 μg/ml Geneticin(Invitrogen 10131-027) and Zeocine 250 μg/ml (Invitrogen, 45-0430).Compounds and reference (CP55,940) were dissolved in DMSO and dilutionswere made in serum free medium containing 2 μM Rolipram (Sigma R6520)and 1 μM Forskolin (Sigma, F3917). 10 μl of each dilution wastransferred to an assay plate (384-well white culture plate, PerkinElmer). Cell suspensions containing 5×10⁵ cells/ml in DMEM/HAMF12containing 1% (v/v) penicillin/streptomycin were prepared fromhCB1_A2-CHO cells and 10 μl (5,000 cells/well) thereof was transferredto the assay plate and cells were incubated for 45 min at 37° C.Homogeneous time-resolved fluorescence (HTRF; CisBio) was used as aread-out by sequentially adding 10 μl cAMP-XL665 and 10 μl anti-cAMP(Eu)cryptate; after 1 h incubation at room temperature, fluorescence at 615nm and 665 nm was measured on Envision (Perkin Elmer). Results werecalculated from the 665 nm/615 nm ratios obtained for the individualcompounds and were compared to values obtained for the referencecompound. The compounds from Examples 12-88, 90, 91, 93 and 94 have anEC₅₀≧1×10⁻⁷ M for CB1.

EXAMPLE 96 The Rat (Chung) Model of Neuropathic Pain

In this model, mechanical allodynia is induced by tight ligation of theleft L5 spinal nerve. This assay has been employed successfully todemonstrate anti-allodynic effects of anticonvulsants (gabapentin),antidepressants (duloxetine) and opioid analgesics (morphine) which areused clinically in the treatment of neuropathic pain.

Male Wistar rats (228-301 g body weight at time of surgery) wereemployed in the study. Rats were placed on an elevated (˜40 cm) meshfloor in perspex boxes and the rats' withdrawal threshold to amechanical stimulus (calibrated von Frey filaments) was measured usingfilaments of increasing force (2.6-167 mN) as described above. The vonFrey filaments were applied to the plantar surface of the paw andthreshold response determined using the up and down method. A positiveresponse was noted if the paw was sharply withdrawn. A cut-off of 15 gwas selected as the upper limit for testing. Following baselinemeasurements each animal was anaesthetised and the L5 spinal nervetightly ligated. The animals were allowed to recover from the surgeryfor a period of at least three days. On the day of drug administrationthe paw withdrawal thresholds were re-measured (0 min). Immediatelyafter this reading, the rats were dosed orally with vehicle or testcompound and readings measured at various time points after compoundadministration.

Data were expressed as mean±s.e.m. Statistical analysis was performedusing the Kruskal-Wallis one-way analysis of variance, a non-parametricstatistical test. Each of the treatment groups were then comparedagainst the vehicle group, using the non-parametric Dunn's test.

As an example, oral administration of the selective CB2 receptor agonist3-isobutyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione(Example 12) attenuated mechanical allodynia in a dose-dependent fashion(Table 1; FIG. 1) at 120 and 180 min post drug administration,respectively. The Minimum effective dose (MED) was 43.8 μmol/kg. Thesedata demonstrate that selective CB2 receptor agonists posses potent oralanti-allodynic activity in a rat model of neuropathic pain.

TABLE 1 Effect of the compound of Example 12 on mechanical allodyniainduced by spinal nerve ligation in rats. Number of Withdrawal Doseanimals threshold (g) at Route (μmol/kg) tested peak effect Vehicle p.o.5 ml · kg⁻¹ 7 1.10 ± 0.22 12 p.o. 4.4 7 2.40 ± 0.64 12 p.o. 13.2 7 4.32± 1.63 12 p.o. 43.8 7  8.97 ± 2.21** Dose groups and number of animalsper group. *p ≦ 0.05 **p ≦ 0.01, Dunns test comparing vehicle-treatedand compound-treated animals.

EXAMPLE 142 Mechanical Hyperalgesia in the Rat

In this rat model of inflammatory pain, inflammation is induced bysubcutaneous injection of complete Freund's adjuvant (CFA) into the hindpaw. The associated mechanical hyperalgesia is quantified by measuringthe reduction in paw withdrawal threshold (PWT) to mechanicalcompression the paw. This assay has been employed successfully todemonstrate anti-hyperalgesic effects of non-steroidal anti-inflammatorydrugs (indomethacin) and coxibs (celecoxib) which are used clinically inthe treatment of inflammatory pain.

Experiments were conducted using male Wistar rats weighing (141-175 g).In brief, the rats' paw withdrawal threshold (PWT) to a mechanicalcompression of the hind paw was measured (baseline reading) using aRandall-Sellito apparatus (Ugo Basile). A cut-off of 20 g was employedto minimise tissue damage to the paw. The animals were then lightlyanaesthetised with isoflurane (1-3%) and complete Freund's adjuvant (0.1ml per paw) was injected subcutaneously (s.c.) into the plantar surfaceof the left hind paw. The animals were then returned to their home cageand left for the inflammation to develop. Twenty four hours after CFAinjection, PWT's were re-measured (0 min) and immediately after thisreading, rats were dosed orally with either vehicle or test compound(4.4-43.8 μmol/kg p.o. of compound 12). Readings were then made at 3 hpost administration. Data were plotted as mean±s.e.m. and comparedbetween groups using the Kruskal-Wallis one-way analysis of variance, anon-parametric statistical test. If statistical significance (P<0.05)was observed with this test, the vehicle group and each of the treatmentgroups were compared using the non-parametric Dunn's test. The percentattenuation of mechanical hyperalgesia is calculated as follows:

${\%\mspace{14mu}{attenuation}\mspace{14mu}{of}\mspace{14mu}{hyperalgesia}} = {\frac{\left( {{{Post}\mspace{14mu}{compound}\mspace{14mu}{PWT}} - {{post}\mspace{14mu}{CFA}\mspace{14mu}{PWT}}} \right)}{\left( {{{Baseline}\mspace{14mu}{PWT}} - {{post}\mspace{14mu}{CFA}\mspace{14mu}{PWT}}} \right)} \times 100}$

Oral administration of compound 12 (4.4-43.8 μmol/kg) reversedmechanical hyperalgesia induced by CFA in a dose-dependent fashion(Table 2). The MED for Org 266919-1 was 13.2 μmol/kg.

These data demonstrate that the selective CB2 receptor agonists possesspotent oral anti-algesic activity in a rat model of inflammatory pain.

TABLE 2 Effect of compound 12 on mechanical hyperalgesia induced bycomplete Freund's adjuvant administered 24 h previously in rats. Numberof % Attenuation of Dose animals hyperalgesia Route (μmol/kg) tested(peak effect) Vehicle p.o. 5 ml · kg⁻¹ 8 −11.05 ± 12.27    12 p.o. 4.4 858.64 ± 27.32  12 p.o. 13.2 9 69.70 ± 12.88* 12 p.o. 43.8 8 116.74 ±23.78** Dose groups and number of animals per group. *p ≦ 0.01 **p ≦0.001, Dunns test comparing vehicle-treated and compound-treatedanimals.

1. A 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative havingthe Formula I

wherein R₁ is H, (C₁₋₆)alkyl (optionally substituted with oxo,(C₁₋₃)alkyloxy, (C₁₋₃)-alkyloxycarbonyl, halogen or CN),(C₃₋₆)cycloalkyl or (C₃₋₆)cycloalkyl(C₁₋₃)alkyl, each cycloalkyl ringoptionally comprising a heteroatom selected from O and S; R₂ and R₃ areindependently H or (C₁₋₃)alkyl; or R₂ and R₃ form together with thecarbon atom to which they are bound a (C₃₋₅)cycloalkyl group; R₄ is H or1 to 3 F substituents; R₅ is H or 1 to 4 F substituents; R₆ and R₇ areindependently H or F; X represents R₈, OR₈, NR₈R₉,

R₈ is (C₅₋₇)cycloalkyl optionally comprising a heteroatom selected fromO, S, SO and SO₂; R₉ is H or (C₁₋₄)alkyl; R₁₀ represents 1-3substituents independently selected from H, (C₁₋₃)alkyl, halogen, oxo,CN and CF₃; Y is CF₂, O, S, SO or SO₂; or a pharmaceutically acceptablesalt thereof.
 2. The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dionederivative of claim 1, wherein R₂, R₃ and R₅ are H.
 3. The1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 1,wherein R₁ is (C₁₋₄)alkyl.
 4. The1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 1,wherein X represents NR₈R₉,


5. The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative ofclaim 4, wherein X is NR₈R₉ and R₈ is cyclohexyl optionally comprising aheteroatom selected from O and S.
 6. The1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 5,wherein R₄ is a F substituent at the position ortho to the CR₆R₇X group.7. The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative ofclaim 1 which is selected from3-Isobutyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-isobutyl-1-(4-(6-(morpholinomethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;1-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione;1-(4-(6-((1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)methyl)pyridin-2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione;1-(4-(6-((1,1-Dioxo-1λ⁶-thiomorpholin-4-yl)methyl)-5-fluoropyridin-2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione;3-Isobutyl-1-(4-(6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-Ethyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-Ethyl-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-ethylimidazolidine-2,4-dione;1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)pyridin-2-yl)benzyl)-3-ethylimidazolidine-2,4-dione;1-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-propylimidazolidine-2,4-dione;1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-propylimidazolidine-2,4-dione;3-(2,2-Difluoroethyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-(2,2-Difluoroethyl)-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-(Cyclopropylmethyl)-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-(Cyclopropylmethyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-(2-Oxopropyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;1-(4-(5-Fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(2-oxopropyl)imidazolidine-2,4-dione;1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-(2-oxopropyl)imidazolidine-2,4-dione;3-Isopropyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-isopropylimidazolidine-2,4-dione;1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)pyridin-2-yl)benzyl)-3-isopropylimidazolidine-2,4-dione;3-Cyclopropyl-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-Cyclopropyl-1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoro-pyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-Cyclobutyl-1-(4-(5-fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-Cyclobutyl-1-(4-(6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-Cyclobutyl-1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)imidazolidine-2,4-dione;3-Cyclobutyl-1-(4-(6-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;1-(4-(6-(Piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;1-(4-(6-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;1-(4-(6-((Tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;and1-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising a1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 1or a pharmaceutically acceptable salt thereof in admixture with one ormore pharmaceutically acceptable auxilliaries.
 9. A pharmaceuticalcomposition comprising a1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 7or a pharmaceutically acceptable salt thereof in admixture with one ormore pharmaceutically acceptable auxilliaries.
 10. A method of treatmentof pain comprising administering to a patient in need thereof atherapeutically effective amount of a1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 1or a pharmaceutically acceptable salt thereof.
 11. The method of claim10 wherein the pain is selected from the group consisting ofperi-operative pain, chronic pain, neuropathic pain, cancer pain andpain and spasticity associated with multiple sclerosis.
 12. A method oftreatment of pain comprising administering to a patient in need thereofa therapeutically effective amount of a1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 7or a pharmaceutically acceptable salt thereof.
 13. The method of claim12 wherein the pain is selected from the group consisting ofperi-operative pain, chronic pain, neuropathic pain, cancer pain andpain and spasticity associated with multiple sclerosis.